NM_031857.2:c.84C>A

Variant names:

• chr5-140848579-C-A
• rs251353
• NM_031857.2:c.84C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0180
• Publications: 28 publications found

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]

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]

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]

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]

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]

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]

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]

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]

PCDHA@ (HGNC:8662):

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3060050.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031857.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA9	NM_031857.2	MANE Select	c.84C>A	p.Ser28Arg	missense	Exon 1 of 4	NP_114063.1	Q9Y5H5-1
	PCDHA1	NM_018900.4	MANE Select	c.2394+59895C>A		intron	N/A	NP_061723.1	Q9Y5I3-1
	PCDHA3	NM_018906.3	MANE Select	c.2394+44988C>A		intron	N/A	NP_061729.1	Q9Y5H8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHA9	ENST00000532602.2	TSL:1 MANE Select	c.84C>A	p.Ser28Arg	missense	Exon 1 of 4	ENSP00000436042.2	Q9Y5H5-1
	PCDHA1	ENST00000504120.4	TSL:1 MANE Select	c.2394+59895C>A		intron	N/A	ENSP00000420840.3	Q9Y5I3-1
	PCDHA3	ENST00000522353.3	TSL:1 MANE Select	c.2394+44988C>A		intron	N/A	ENSP00000429808.2	Q9Y5H8-1

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

GnomAD2 exomes AF: 0.520 AC: 128578 AN: 247162 AF XY: 0.530

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 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

African (AFR) AF: 0.272 AC: 9078 AN: 33330

American (AMR) AF: 0.492 AC: 21732 AN: 44190

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 13965 AN: 25546

East Asian (EAS) AF: 0.486 AC: 19280 AN: 39668

South Asian (SAS) AF: 0.617 AC: 52641 AN: 85358

European-Finnish (FIN) AF: 0.582 AC: 30686 AN: 52770

Middle Eastern (MID) AF: 0.530 AC: 2965 AN: 5596

European-Non Finnish (NFE) AF: 0.530 AC: 581187 AN: 1096268

Other (OTH) AF: 0.519 AC: 30930 AN: 59610

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

African (AFR) AF: 0.273 AC: 11189 AN: 40956

American (AMR) AF: 0.502 AC: 7500 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1863 AN: 3402

East Asian (EAS) AF: 0.475 AC: 2437 AN: 5128

South Asian (SAS) AF: 0.631 AC: 2969 AN: 4706

European-Finnish (FIN) AF: 0.569 AC: 5878 AN: 10334

Middle Eastern (MID) AF: 0.479 AC: 138 AN: 288

European-Non Finnish (NFE) AF: 0.533 AC: 35544 AN: 66710

Other (OTH) AF: 0.472 AC: 981 AN: 2078

Alfa AF: 0.00 Hom.: 0

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

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PCDHA9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.018
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.088
Sift	Benign	0.049	D
Sift4G	Benign	0.075	T
Polyphen		0.0060	B
Vest4		0.076
MutPred		0.28		Loss of glycosylation at S28 (P = 0.0574)
ClinPred		0.015	T
GERP RS		2.9
PromoterAI		0.0099	Neutral
Varity_R		0.43
gMVP		0.46
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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