10-71777631-T-C

Variant names:

• chr10-71777631-T-C
• rs7917781
• NM_022124.6:c.4846-49T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.4846-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 1,525,420 control chromosomes in the GnomAD database, including 156,751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13259 hom., cov: 31)
  • Exomes 𝑓: 0.46 (143492 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.720
• Publications: 10 publications found

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

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

  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

ENSG00000306531 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-71777631-T-C is Benign according to our data. Variant chr10-71777631-T-C is described in ClinVar as Benign. ClinVar VariationId is 261550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.4846-49T>C		intron_variant	Intron 38 of 69	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.4846-49T>C		intron_variant	Intron 38 of 69	5	NM_022124.6	ENSP00000224721.9
ENSG00000306531	ENST00000819235.1	n.158-566A>G		intron_variant	Intron 1 of 1
ENSG00000306531	ENST00000819236.1	n.157-463A>G		intron_variant	Intron 1 of 1
ENSG00000306531	ENST00000819237.1	n.146-561A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62966 AN: 151864 Hom.: 13246 Cov.: 31

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.410

GnomAD2 exomes AF: 0.442 AC: 77644 AN: 175702 AF XY: 0.436

Gnomad AFR exome AF: 0.328

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.490

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.455 AC: 625185 AN: 1373438 Hom.: 143492 Cov.: 24 AF XY: 0.452 AC XY: 307274 AN XY: 679684

African (AFR) AF: 0.327 AC: 10261 AN: 31364

American (AMR) AF: 0.476 AC: 17740 AN: 37232

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 10501 AN: 24980

East Asian (EAS) AF: 0.522 AC: 19009 AN: 36422

South Asian (SAS) AF: 0.382 AC: 30201 AN: 79026

European-Finnish (FIN) AF: 0.453 AC: 22615 AN: 49904

Middle Eastern (MID) AF: 0.315 AC: 1349 AN: 4288

European-Non Finnish (NFE) AF: 0.464 AC: 488171 AN: 1053002

Other (OTH) AF: 0.443 AC: 25338 AN: 57220

GnomAD4 genome AF: 0.415 AC: 63012 AN: 151982 Hom.: 13259 Cov.: 31 AF XY: 0.413 AC XY: 30673 AN XY: 74266

African (AFR) AF: 0.336 AC: 13914 AN: 41430

American (AMR) AF: 0.418 AC: 6383 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1445 AN: 3468

East Asian (EAS) AF: 0.481 AC: 2473 AN: 5144

South Asian (SAS) AF: 0.379 AC: 1830 AN: 4826

European-Finnish (FIN) AF: 0.454 AC: 4797 AN: 10556

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30816 AN: 67964

Other (OTH) AF: 0.408 AC: 861 AN: 2112

Alfa AF: 0.436 Hom.: 41117

Bravo AF: 0.411

Asia WGS AF: 0.406 AC: 1412 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 12 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.52
PhyloP100		-0.72
Mutation Taster		=100/0	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: rs7917781; hg19: chr10-73537388; COSMIC: COSV56479419; COSMIC: COSV56479419;