NM_033056.4:c.1917+33_1917+34dupGT

Variant names:

• chr10-54132840-T-TAC
• rs5785040
• NM_033056.4:c.1917+33_1917+34dupGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.1917+33_1917+34dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,470,580 control chromosomes in the GnomAD database, including 7,105 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1897 hom., cov: 0)
  • Exomes 𝑓: 0.14 (5208 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 10-54132840-T-TAC is Benign according to our data. Variant chr10-54132840-T-TAC is described in ClinVar as Benign. ClinVar VariationId is 227007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1917+33_1917+34dupGT		intron_variant	Intron 15 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1917+33_1917+34dupGT		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+35insGT		intron_variant	Intron 15 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1917+34_1917+35insGT		intron_variant	Intron 15 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23468 AN: 150306 Hom.: 1894 Cov.: 0

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0878

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.198 AC: 27706 AN: 140090 AF XY: 0.191

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.342

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.137 AC: 180874 AN: 1320168 Hom.: 5208 Cov.: 31 AF XY: 0.136 AC XY: 89074 AN XY: 653880

African (AFR) AF: 0.186 AC: 5640 AN: 30308

American (AMR) AF: 0.245 AC: 8960 AN: 36632

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3317 AN: 23658

East Asian (EAS) AF: 0.339 AC: 9688 AN: 28612

South Asian (SAS) AF: 0.108 AC: 8116 AN: 75202

European-Finnish (FIN) AF: 0.0982 AC: 4690 AN: 47736

Middle Eastern (MID) AF: 0.154 AC: 832 AN: 5388

European-Non Finnish (NFE) AF: 0.129 AC: 131359 AN: 1017678

Other (OTH) AF: 0.151 AC: 8272 AN: 54954

GnomAD4 genome AF: 0.156 AC: 23497 AN: 150412 Hom.: 1897 Cov.: 0 AF XY: 0.156 AC XY: 11459 AN XY: 73422

African (AFR) AF: 0.193 AC: 7908 AN: 40962

American (AMR) AF: 0.199 AC: 2999 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3446

East Asian (EAS) AF: 0.288 AC: 1463 AN: 5074

South Asian (SAS) AF: 0.109 AC: 520 AN: 4762

European-Finnish (FIN) AF: 0.0878 AC: 906 AN: 10320

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.128 AC: 8648 AN: 67476

Other (OTH) AF: 0.171 AC: 356 AN: 2082

Alfa AF: 0.100 Hom.: 79

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 08, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1917+13GT[12] in intron 15 of PCDH15: This variant is not expected to have cli nical significance because it is not located within the splice consensus sequenc e. It has been detected in 17.5% (8259/47276) of chromosomes across several dive rse populations by the Exome Aggregate Consortium (http://exac.broadinstitute.or g/variant/10-55892600-T-TAC). -

not provided Benign:1

Aug 13, 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;