rs3756337

Positions:

• chr5-140806853-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018900.4(PCDHA1):​c.2394+18169G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 296,122 control chromosomes in the GnomAD database, including 31,281 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14580 hom., cov: 34)
  • Exomes 𝑓: 0.47 (16701 hom.)
• Consequence: PCDHA1 NM_018900.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.66

Genes affected

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]

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]

ENSG00000279726 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA1	NM_018900.4	c.2394+18169G>C		intron_variant		ENST00000504120.4	NP_061723.1
PCDHA3	NM_018906.3	c.2394+3262G>C		intron_variant		ENST00000522353.3	NP_061729.1
PCDHA2	NM_018905.3	c.2388+9501G>C		intron_variant		ENST00000526136.2	NP_061728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA1	ENST00000504120.4	c.2394+18169G>C		intron_variant		1	NM_018900.4	ENSP00000420840.3
PCDHA3	ENST00000522353.3	c.2394+3262G>C		intron_variant		1	NM_018906.3	ENSP00000429808.2
PCDHA2	ENST00000526136.2	c.2388+9501G>C		intron_variant		1	NM_018905.3	ENSP00000431748.1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65454 AN: 151994 Hom.: 14579 Cov.: 34

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.472 AC: 68020 AN: 144010 Hom.: 16701 AF XY: 0.476 AC XY: 34839 AN XY: 73172

Gnomad4 AFR exome AF: 0.349

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.485

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.553

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.471

Gnomad4 OTH exome AF: 0.463

GnomAD4 genome AF: 0.430 AC: 65464 AN: 152112 Hom.: 14580 Cov.: 34 AF XY: 0.429 AC XY: 31900 AN XY: 74356

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.474

Gnomad4 EAS AF: 0.520

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.440

Alfa AF: 0.445 Hom.: 1880

Bravo AF: 0.439

Asia WGS AF: 0.436 AC: 1517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.35

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: rs3756337; hg19: chr5-140186438; COSMIC: COSV63539982; COSMIC: COSV63539982;