10-54132840-TACACACACACAC-TACACACACACACACACAC

Variant names:

• chr10-54132840-T-TACACAC
• rs5785040
• NM_033056.4:c.1917+29_1917+34dupGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_033056.4(PCDH15):​c.1917+29_1917+34dupGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,494,628 control chromosomes in the GnomAD database, including 361 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (60 hom., cov: 0)
  • Exomes 𝑓: 0.038 (301 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-TACACAC is Benign according to our data. Variant chr10-54132840-T-TACACAC is described in ClinVar as Benign. ClinVar VariationId is 1294168.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0264 (3976/150496) while in subpopulation NFE AF = 0.0421 (2839/67496). AF 95% confidence interval is 0.0408. There are 60 homozygotes in GnomAd4. There are 1902 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1917+29_1917+34dupGTGTGT		intron_variant	Intron 15 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1917+29_1917+34dupGTGTGT		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+35insGTGTGT		intron_variant	Intron 15 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1917+34_1917+35insGTGTGT		intron_variant	Intron 15 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 3983 AN: 150388 Hom.: 63 Cov.: 0

Gnomad AFR AF: 0.00692

Gnomad AMI AF: 0.0133

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0449

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0237

GnomAD2 exomes AF: 0.0375 AC: 5249 AN: 140090 AF XY: 0.0390

Gnomad AFR exome AF: 0.00795

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.0152

Gnomad FIN exome AF: 0.0327

Gnomad NFE exome AF: 0.0547

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0379 AC: 50944 AN: 1344132 Hom.: 301 Cov.: 31 AF XY: 0.0379 AC XY: 25219 AN XY: 665982

African (AFR) AF: 0.00647 AC: 198 AN: 30610

American (AMR) AF: 0.0161 AC: 594 AN: 36896

Ashkenazi Jewish (ASJ) AF: 0.0379 AC: 906 AN: 23882

East Asian (EAS) AF: 0.00947 AC: 323 AN: 34094

South Asian (SAS) AF: 0.0238 AC: 1847 AN: 77598

European-Finnish (FIN) AF: 0.0283 AC: 1373 AN: 48472

Middle Eastern (MID) AF: 0.0372 AC: 202 AN: 5424

European-Non Finnish (NFE) AF: 0.0422 AC: 43529 AN: 1031342

Other (OTH) AF: 0.0353 AC: 1972 AN: 55814

GnomAD4 genome AF: 0.0264 AC: 3976 AN: 150496 Hom.: 60 Cov.: 0 AF XY: 0.0259 AC XY: 1902 AN XY: 73470

African (AFR) AF: 0.00690 AC: 283 AN: 40994

American (AMR) AF: 0.0152 AC: 229 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 135 AN: 3446

East Asian (EAS) AF: 0.00925 AC: 47 AN: 5082

South Asian (SAS) AF: 0.0220 AC: 105 AN: 4762

European-Finnish (FIN) AF: 0.0259 AC: 268 AN: 10328

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0421 AC: 2839 AN: 67496

Other (OTH) AF: 0.0235 AC: 49 AN: 2086

Alfa AF: 0.0260 Hom.: 79

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

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;