5-140848888-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_031857.2(PCDHA9):c.393A>G(p.Pro131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (63 hom., cov: 23)
  • Exomes 𝑓: 0.015 (5731 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDHA9 NM_031857.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -11.9

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-140848888-A-G is Benign according to our data. Variant chr5-140848888-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3037401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-11.9 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 62 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA9	NM_031857.2	c.393A>G	p.Pro131=	synonymous_variant	1/4	ENST00000532602.2
PCDHA1	NM_018900.4	c.2394+60204A>G		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+51536A>G		intron_variant		ENST00000526136.2
PCDHA3	NM_018906.3	c.2394+45297A>G		intron_variant		ENST00000522353.3
PCDHA4	NM_018907.4	c.2385+39316A>G		intron_variant		ENST00000530339.2
PCDHA5	NM_018908.3	c.2352+24761A>G		intron_variant		ENST00000529859.2
PCDHA6	NM_018909.4	c.2394+18403A>G		intron_variant		ENST00000529310.6
PCDHA7	NM_018910.3	c.2355+12150A>G		intron_variant		ENST00000525929.2
PCDHA8	NM_018911.3	c.2394+5173A>G		intron_variant		ENST00000531613.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA9	ENST00000532602.2	c.393A>G	p.Pro131=	synonymous_variant	1/4	1	NM_031857.2	P1
PCDHA1	ENST00000504120.4	c.2394+60204A>G		intron_variant		1	NM_018900.4	P1
PCDHA3	ENST00000522353.3	c.2394+45297A>G		intron_variant		1	NM_018906.3	P1
PCDHA7	ENST00000525929.2	c.2355+12150A>G		intron_variant		1	NM_018910.3	P1
PCDHA2	ENST00000526136.2	c.2388+51536A>G		intron_variant		1	NM_018905.3	P1
PCDHA6	ENST00000529310.6	c.2394+18403A>G		intron_variant		1	NM_018909.4	P1
PCDHA5	ENST00000529859.2	c.2352+24761A>G		intron_variant		1	NM_018908.3	P1
PCDHA4	ENST00000530339.2	c.2385+39316A>G		intron_variant		1	NM_018907.4	P1
PCDHA8	ENST00000531613.2	c.2394+5173A>G		intron_variant		1	NM_018911.3	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1783 AN: 139128 Hom.: 62 Cov.: 23

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00115

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0278

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00541 AC: 1335 AN: 246730 Hom.: 195 AF XY: 0.00541 AC XY: 722 AN XY: 133386

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00174

Gnomad SAS exome AF: 0.00372

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00549

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0150 AC: 20680 AN: 1374976 Hom.: 5731 Cov.: 34 AF XY: 0.0149 AC XY: 10232 AN XY: 684694

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.00275

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0128 AC: 1785 AN: 139250 Hom.: 63 Cov.: 23 AF XY: 0.0141 AC XY: 958 AN XY: 68036

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00157

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0265

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.0129

Alfa AF: 0.0364 Hom.: 29

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 25, 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
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.2
Dann	Benign	0.47

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: rs364063; hg19: chr5-140228473; COSMIC: COSV65326107; COSMIC: COSV65326107;