5-140848579-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031857.2(PCDHA9):c.84C>A(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,591,790 control chromosomes in the GnomAD database, including 256,408 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.46 (19495 hom., cov: 31)
  • Exomes 𝑓: 0.53 (236913 hom.)
• Consequence: PCDHA9 NM_031857.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0180

Genes affected

PCDHA9 (HGNC:8675): (protocadherin alpha 9) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA2 (HGNC:8668): (protocadherin alpha 2) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA3 (HGNC:8669): (protocadherin alpha 3) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA4 (HGNC:8670): (protocadherin alpha 4) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA5 (HGNC:8671): (protocadherin alpha 5) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA6 (HGNC:8672): (protocadherin alpha 6) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA7 (HGNC:8673): (protocadherin alpha 7) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA8 (HGNC:8674): (protocadherin alpha 8) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.24073185E-5).
• BP6: Variant 5-140848579-C-A is Benign according to our data. Variant chr5-140848579-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3060050.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA9	NM_031857.2	c.84C>A	p.Ser28Arg	missense_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+59895C>A		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+51227C>A		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+44988C>A		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39007C>A		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+24452C>A		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+18094C>A		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+11841C>A		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+4864C>A		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.84C>A	p.Ser28Arg	missense_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+59895C>A		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+44988C>A		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+11841C>A		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+51227C>A		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+18094C>A		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+24452C>A		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39007C>A		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+4864C>A		intron_variant		1	NM_018911.3	P1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 68684 AN: 149336 Hom.: 19476 Cov.: 31

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.461

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.520 AC: 128578 AN: 247162 Hom.: 39140 AF XY: 0.530 AC XY: 70830 AN XY: 133656

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.470

Gnomad SAS exome AF: 0.622

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.532

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.529 AC: 762464 AN: 1442336 Hom.: 236913 Cov.: 91 AF XY: 0.532 AC XY: 381575 AN XY: 717660

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.492

Gnomad4 ASJ exome AF: 0.547

Gnomad4 EAS exome AF: 0.486

Gnomad4 SAS exome AF: 0.617

Gnomad4 FIN exome AF: 0.582

Gnomad4 NFE exome AF: 0.530

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.460 AC: 68728 AN: 149454 Hom.: 19495 Cov.: 31 AF XY: 0.463 AC XY: 33808 AN XY: 72960

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.548

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.631

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.472

ESP6500AA AF: 0.262 AC: 1153

ESP6500EA AF: 0.537 AC: 4581

ExAC AF: 0.518 AC: 62464

Asia WGS AF: 0.593 AC: 2053 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PCDHA9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.027	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.000012	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	3.9e-12	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.088
Sift	Benign	0.049	D;D
Sift4G	Benign	0.075	T;D
Polyphen		0.0060	B;B
Vest4		0.076
MutPred		0.28		Loss of glycosylation at S28 (P = 0.0574);Loss of glycosylation at S28 (P = 0.0574);
ClinPred		0.015	T
GERP RS		2.9
Varity_R		0.43
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs251353; hg19: chr5-140228164; COSMIC: COSV65323402; COSMIC: COSV65323402;