NM_033056.4:c.1917+31_1917+34dupGTGT

Variant names:

• chr10-54132840-T-TACAC
• rs5785040
• NM_033056.4:c.1917+31_1917+34dupGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_033056.4(PCDH15):​c.1917+31_1917+34dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,493,460 control chromosomes in the GnomAD database, including 6,173 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (1496 hom., cov: 0)
  • Exomes 𝑓: 0.11 (4677 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0900
• Publications: 2 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, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -10 ACMG points.

• BP6: Variant 10-54132840-T-TACAC is Benign according to our data. Variant chr10-54132840-T-TACAC is described in ClinVar as Benign. ClinVar VariationId is 1294167.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1917+31_1917+34dupGTGT		intron_variant	Intron 15 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1917+31_1917+34dupGTGT		intron_variant	Intron 15 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1917+34_1917+35insGTGT		intron_variant	Intron 15 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1917+34_1917+35insGTGT		intron_variant	Intron 15 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15431 AN: 150344 Hom.: 1502 Cov.: 0

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.0266

Gnomad AMR AF: 0.0658

Gnomad ASJ AF: 0.0682

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0861

Gnomad OTH AF: 0.0887

GnomAD2 exomes AF: 0.148 AC: 20784 AN: 140090 AF XY: 0.156

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.0792

Gnomad ASJ exome AF: 0.0962

Gnomad EAS exome AF: 0.439

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.109 AC: 146512 AN: 1343008 Hom.: 4677 Cov.: 31 AF XY: 0.111 AC XY: 74098 AN XY: 665366

African (AFR) AF: 0.0572 AC: 1748 AN: 30568

American (AMR) AF: 0.0656 AC: 2416 AN: 36838

Ashkenazi Jewish (ASJ) AF: 0.0722 AC: 1723 AN: 23870

East Asian (EAS) AF: 0.479 AC: 16439 AN: 34298

South Asian (SAS) AF: 0.198 AC: 15403 AN: 77622

European-Finnish (FIN) AF: 0.152 AC: 7334 AN: 48366

Middle Eastern (MID) AF: 0.0618 AC: 335 AN: 5422

European-Non Finnish (NFE) AF: 0.0919 AC: 94632 AN: 1030262

Other (OTH) AF: 0.116 AC: 6482 AN: 55762

GnomAD4 genome AF: 0.102 AC: 15415 AN: 150452 Hom.: 1496 Cov.: 0 AF XY: 0.111 AC XY: 8124 AN XY: 73448

African (AFR) AF: 0.0588 AC: 2408 AN: 40982

American (AMR) AF: 0.0656 AC: 991 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.0682 AC: 235 AN: 3446

East Asian (EAS) AF: 0.574 AC: 2912 AN: 5074

South Asian (SAS) AF: 0.238 AC: 1133 AN: 4758

European-Finnish (FIN) AF: 0.165 AC: 1707 AN: 10326

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0861 AC: 5810 AN: 67478

Other (OTH) AF: 0.0887 AC: 185 AN: 2086

Alfa AF: 0.0590 Hom.: 79

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.090
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5785040; hg19: chr10-55892600;