rs41274634

Variant names:

• chr10-54236848-T-C
• rs41274634
• NM_033056.4:c.960A>G

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.960A>G​(p.Pro320Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,613,256 control chromosomes in the GnomAD database, including 951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 32)
  • Exomes 𝑓: 0.030 (889 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.818
• Publications: 8 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=-0.63).
• BP6: Variant 10-54236848-T-C is Benign according to our data. Variant chr10-54236848-T-C is described in ClinVar as Benign. ClinVar VariationId is 46513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.818 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0715 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.960A>G	p.Pro320Pro	synonymous	Exon 9 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.960A>G	p.Pro320Pro	synonymous	Exon 9 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.975A>G	p.Pro325Pro	synonymous	Exon 10 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.960A>G	p.Pro320Pro	synonymous	Exon 9 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.960A>G	p.Pro320Pro	synonymous	Exon 9 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.960A>G	p.Pro320Pro	synonymous	Exon 9 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3851 AN: 152138 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0784

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0301 AC: 7560 AN: 251394 AF XY: 0.0326

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.0394

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0297 AC: 43321 AN: 1461000 Hom.: 889 Cov.: 31 AF XY: 0.0311 AC XY: 22580 AN XY: 726864

African (AFR) AF: 0.0192 AC: 641 AN: 33458

American (AMR) AF: 0.0353 AC: 1577 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00957 AC: 250 AN: 26120

East Asian (EAS) AF: 0.00129 AC: 51 AN: 39658

South Asian (SAS) AF: 0.0809 AC: 6978 AN: 86224

European-Finnish (FIN) AF: 0.0165 AC: 881 AN: 53416

Middle Eastern (MID) AF: 0.0245 AC: 141 AN: 5764

European-Non Finnish (NFE) AF: 0.0281 AC: 31189 AN: 1111274

Other (OTH) AF: 0.0267 AC: 1613 AN: 60364

GnomAD4 genome AF: 0.0253 AC: 3859 AN: 152256 Hom.: 62 Cov.: 32 AF XY: 0.0263 AC XY: 1959 AN XY: 74430

African (AFR) AF: 0.0216 AC: 896 AN: 41574

American (AMR) AF: 0.0343 AC: 524 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5182

South Asian (SAS) AF: 0.0780 AC: 376 AN: 4820

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1787 AN: 67978

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0256 Hom.: 113

Bravo AF: 0.0240

Asia WGS AF: 0.0400 AC: 141 AN: 3478

EpiCase AF: 0.0244

EpiControl AF: 0.0207

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.2
DANN	Benign	0.62
PhyloP100		-0.82
Mutation Taster		=87/13	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: rs41274634; hg19: chr10-55996608;