rs7921598

Variant names:

• chr10-54195725-A-G
• rs7921598
• NM_033056.4:c.1263T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001384140.1(PCDH15):​c.1263T>C​(p.Thr421Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,080 control chromosomes in the GnomAD database, including 23,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (6057 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17371 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.223
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-54195725-A-G is Benign according to our data. Variant chr10-54195725-A-G is described in ClinVar as Benign. ClinVar VariationId is 46439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.223 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

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_033056.4	MANE Plus Clinical	c.1263T>C	p.Thr421Thr	synonymous	Exon 11 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1263T>C	p.Thr421Thr	synonymous	Exon 11 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1278T>C	p.Thr426Thr	synonymous	Exon 12 of 35	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.1263T>C	p.Thr421Thr	synonymous	Exon 11 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1263T>C	p.Thr421Thr	synonymous	Exon 11 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1263T>C	p.Thr421Thr	synonymous	Exon 11 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.230 AC: 35002 AN: 151942 Hom.: 6041 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0910

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.208

GnomAD2 exomes AF: 0.165 AC: 41539 AN: 251378 AF XY: 0.158

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.0950

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.140 AC: 203946 AN: 1461022 Hom.: 17371 Cov.: 33 AF XY: 0.139 AC XY: 100829 AN XY: 726858

African (AFR) AF: 0.504 AC: 16856 AN: 33440

American (AMR) AF: 0.212 AC: 9470 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3112 AN: 26122

East Asian (EAS) AF: 0.0669 AC: 2655 AN: 39670

South Asian (SAS) AF: 0.179 AC: 15448 AN: 86230

European-Finnish (FIN) AF: 0.113 AC: 6014 AN: 53418

Middle Eastern (MID) AF: 0.174 AC: 1002 AN: 5760

European-Non Finnish (NFE) AF: 0.126 AC: 139956 AN: 1111292

Other (OTH) AF: 0.156 AC: 9433 AN: 60370

GnomAD4 genome AF: 0.231 AC: 35063 AN: 152058 Hom.: 6057 Cov.: 32 AF XY: 0.226 AC XY: 16830 AN XY: 74326

African (AFR) AF: 0.488 AC: 20230 AN: 41416

American (AMR) AF: 0.199 AC: 3047 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3472

East Asian (EAS) AF: 0.0910 AC: 470 AN: 5166

South Asian (SAS) AF: 0.181 AC: 870 AN: 4818

European-Finnish (FIN) AF: 0.108 AC: 1146 AN: 10606

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8305 AN: 67992

Other (OTH) AF: 0.211 AC: 445 AN: 2110

Alfa AF: 0.160 Hom.: 10427

Bravo AF: 0.253

Asia WGS AF: 0.163 AC: 569 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.124

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.36
PhyloP100		-0.22
PromoterAI		-0.025	Neutral
Mutation Taster		=98/2	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: rs7921598; hg19: chr10-55955485; COSMIC: COSV57302866;