NM_001384140.1:c.4640G>A

Variant names:

• chr10-53810587-C-T
• rs41274622
• NM_001384140.1:c.4640G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384140.1(PCDH15):​c.4640G>A​(p.Gly1547Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00944 in 1,613,770 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (82 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.53
• Publications: 7 publications found

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00866279).
• BP6: Variant 10-53810587-C-T is Benign according to our data. Variant chr10-53810587-C-T is described in ClinVar as Benign. ClinVar VariationId is 227001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00717 (1092/152268) while in subpopulation NFE AF = 0.0107 (727/68016). AF 95% confidence interval is 0.01. There are 11 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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
	PCDH15	NM_001384140.1	MANE Select	c.4640G>A	p.Gly1547Asp	missense	Exon 37 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142769.3		c.4487G>A	p.Gly1496Asp	missense	Exon 36 of 37	NP_001136241.1	A0A087WZN9
	PCDH15	NM_001354411.2		c.4466G>A	p.Gly1489Asp	missense	Exon 34 of 35	NP_001341340.1	Q96QU1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000644397.2	MANE Select	c.4640G>A	p.Gly1547Asp	missense	Exon 37 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.4466G>A	p.Gly1489Asp	missense	Exon 34 of 35	ENSP00000378832.2	Q96QU1-4
	PCDH15	ENST00000616114.4	TSL:1	c.4445G>A	p.Gly1482Asp	missense	Exon 33 of 34	ENSP00000483745.1	Q96QU1-6

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1092 AN: 152150 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00767 AC: 1908 AN: 248774 AF XY: 0.00761

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00694

GnomAD4 exome AF: 0.00967 AC: 14138 AN: 1461502 Hom.: 82 Cov.: 31 AF XY: 0.00921 AC XY: 6698 AN XY: 727044

African (AFR) AF: 0.00182 AC: 61 AN: 33478

American (AMR) AF: 0.00340 AC: 152 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 147 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86256

European-Finnish (FIN) AF: 0.0152 AC: 811 AN: 53336

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12420 AN: 1111756

Other (OTH) AF: 0.00785 AC: 474 AN: 60370

GnomAD4 genome AF: 0.00717 AC: 1092 AN: 152268 Hom.: 11 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74452

African (AFR) AF: 0.00171 AC: 71 AN: 41540

American (AMR) AF: 0.00530 AC: 81 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 727 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00958 Hom.: 19

Bravo AF: 0.00635

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 5

ESP6500EA AF: 0.0120 AC: 86

ExAC AF: 0.00792 AC: 955

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0074	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.5
REVEL	Benign	0.094
Sift4G	Benign	0.40	T
Vest4		0.41
MVP		0.46
ClinPred		0.069	T
GERP RS		4.2
PromoterAI		0.023	Neutral
Mutation Taster		=89/11	polymorphism

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: rs41274622; hg19: chr10-55570347; COSMIC: COSV64706061;