10-71695551-T-C

Variant names:

• chr10-71695551-T-C
• rs3752750
• NM_022124.6:c.2397+26T>C

Variant summary

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

The ENST00000224721.12(CDH23):​c.2397+26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,532,188 control chromosomes in the GnomAD database, including 351,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30278 hom., cov: 35)
  • Exomes 𝑓: 0.68 (320955 hom.)
• Consequence: CDH23 ENST00000224721.12 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.83
• Publications: 8 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-71695551-T-C is Benign according to our data. Variant chr10-71695551-T-C is described in ClinVar as Benign. ClinVar VariationId is 261545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000224721.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.2397+26T>C		intron	N/A	NP_071407.4
	CDH23	NM_001171930.2		c.2397+26T>C		intron	N/A	NP_001165401.1
	CDH23	NM_001171931.2		c.2397+26T>C		intron	N/A	NP_001165402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2397+26T>C		intron	N/A	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.2397+26T>C		intron	N/A	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.2397+26T>C		intron	N/A	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.625 AC: 95011 AN: 152046 Hom.: 30270 Cov.: 35

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.654

GnomAD2 exomes AF: 0.628 AC: 155281 AN: 247240 AF XY: 0.640

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.501

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.711

Gnomad OTH exome AF: 0.656

GnomAD4 exome AF: 0.678 AC: 934982 AN: 1380024 Hom.: 320955 Cov.: 22 AF XY: 0.679 AC XY: 469048 AN XY: 690952

African (AFR) AF: 0.507 AC: 16187 AN: 31930

American (AMR) AF: 0.475 AC: 21141 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 19678 AN: 25558

East Asian (EAS) AF: 0.476 AC: 18713 AN: 39300

South Asian (SAS) AF: 0.633 AC: 53621 AN: 84774

European-Finnish (FIN) AF: 0.566 AC: 29957 AN: 52950

Middle Eastern (MID) AF: 0.700 AC: 3925 AN: 5610

European-Non Finnish (NFE) AF: 0.707 AC: 733307 AN: 1037584

Other (OTH) AF: 0.665 AC: 38453 AN: 57802

GnomAD4 genome AF: 0.625 AC: 95050 AN: 152164 Hom.: 30278 Cov.: 35 AF XY: 0.617 AC XY: 45904 AN XY: 74392

African (AFR) AF: 0.528 AC: 21904 AN: 41510

American (AMR) AF: 0.563 AC: 8609 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2712 AN: 3472

East Asian (EAS) AF: 0.476 AC: 2459 AN: 5170

South Asian (SAS) AF: 0.618 AC: 2985 AN: 4830

European-Finnish (FIN) AF: 0.553 AC: 5860 AN: 10588

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48353 AN: 67988

Other (OTH) AF: 0.650 AC: 1372 AN: 2110

Alfa AF: 0.678 Hom.: 7391

Bravo AF: 0.622

Asia WGS AF: 0.522 AC: 1818 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.053
DANN	Benign	0.23
PhyloP100		-4.8
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: rs3752750; hg19: chr10-73455308;