10-54346413-T-C

Variant names:

• chr10-54346413-T-C
• rs34164469
• NM_033056.4:c.546A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001384140.1(PCDH15):​c.546A>G​(p.Gly182Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,494 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G182G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (21 hom., cov: 32)
  • Exomes 𝑓: 0.020 (316 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.352
• Publications: 3 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=-0.54).
• BP6: Variant 10-54346413-T-C is Benign according to our data. Variant chr10-54346413-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0148 (2259/152312) while in subpopulation NFE AF = 0.023 (1567/68028). AF 95% confidence interval is 0.0221. There are 21 homozygotes in GnomAd4. There are 1038 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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_033056.4	MANE Plus Clinical	c.546A>G	p.Gly182Gly	synonymous	Exon 6 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.546A>G	p.Gly182Gly	synonymous	Exon 6 of 38	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.561A>G	p.Gly187Gly	synonymous	Exon 7 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.546A>G	p.Gly182Gly	synonymous	Exon 6 of 33	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.546A>G	p.Gly182Gly	synonymous	Exon 6 of 38	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.546A>G	p.Gly182Gly	synonymous	Exon 6 of 35	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2259 AN: 152194 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0138 AC: 3480 AN: 251318 AF XY: 0.0136

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0195 AC: 28506 AN: 1461182 Hom.: 316 Cov.: 30 AF XY: 0.0190 AC XY: 13780 AN XY: 726914

African (AFR) AF: 0.00317 AC: 106 AN: 33466

American (AMR) AF: 0.0116 AC: 520 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 685 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00327 AC: 282 AN: 86246

European-Finnish (FIN) AF: 0.00435 AC: 232 AN: 53352

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5766

European-Non Finnish (NFE) AF: 0.0230 AC: 25576 AN: 1111466

Other (OTH) AF: 0.0178 AC: 1074 AN: 60374

GnomAD4 genome AF: 0.0148 AC: 2259 AN: 152312 Hom.: 21 Cov.: 32 AF XY: 0.0139 AC XY: 1038 AN XY: 74472

African (AFR) AF: 0.00455 AC: 189 AN: 41576

American (AMR) AF: 0.0184 AC: 281 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0230 AC: 1567 AN: 68028

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0193 Hom.: 59

Bravo AF: 0.0154

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0255

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	3	Usher syndrome type 1F (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.5
DANN	Benign	0.72
PhyloP100		-0.35
Mutation Taster		=88/12	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: rs34164469; hg19: chr10-56106173;