10-71739804-C-G

Variant names:

• chr10-71739804-C-G
• rs10762474
• NM_022124.6:c.4488+32C>G

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.4488+32C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,582,254 control chromosomes in the GnomAD database, including 244,844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20464 hom., cov: 33)
  • Exomes 𝑓: 0.56 (224380 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.610
• 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=-0.91).
• BP6: Variant 10-71739804-C-G is Benign according to our data. Variant chr10-71739804-C-G is described in ClinVar as Benign. ClinVar VariationId is 261549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. 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.4488+32C>G		intron	N/A	NP_071407.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4488+32C>G		intron	N/A	ENSP00000224721.9
	CDH23	ENST00000398792.3	TSL:2	n.1177+32C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77684 AN: 151968 Hom.: 20466 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.501 AC: 116078 AN: 231556 AF XY: 0.509

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.305

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.530

GnomAD4 exome AF: 0.555 AC: 793870 AN: 1430168 Hom.: 224380 Cov.: 33 AF XY: 0.554 AC XY: 392103 AN XY: 708262

African (AFR) AF: 0.405 AC: 13360 AN: 32958

American (AMR) AF: 0.361 AC: 15655 AN: 43372

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 15092 AN: 25288

East Asian (EAS) AF: 0.271 AC: 10619 AN: 39192

South Asian (SAS) AF: 0.455 AC: 38273 AN: 84156

European-Finnish (FIN) AF: 0.564 AC: 25492 AN: 45172

Middle Eastern (MID) AF: 0.536 AC: 3047 AN: 5684

European-Non Finnish (NFE) AF: 0.585 AC: 640444 AN: 1095154

Other (OTH) AF: 0.539 AC: 31888 AN: 59192

GnomAD4 genome AF: 0.511 AC: 77693 AN: 152086 Hom.: 20464 Cov.: 33 AF XY: 0.508 AC XY: 37738 AN XY: 74360

African (AFR) AF: 0.414 AC: 17184 AN: 41466

American (AMR) AF: 0.451 AC: 6896 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2065 AN: 3468

East Asian (EAS) AF: 0.287 AC: 1484 AN: 5170

South Asian (SAS) AF: 0.460 AC: 2220 AN: 4826

European-Finnish (FIN) AF: 0.562 AC: 5948 AN: 10582

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.591 AC: 40145 AN: 67984

Other (OTH) AF: 0.533 AC: 1126 AN: 2114

Alfa AF: 0.510 Hom.: 2858

Bravo AF: 0.498

Asia WGS AF: 0.344 AC: 1198 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	-0.91
CADD	Benign	0.50
DANN	Benign	0.47
PhyloP100		-0.61
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: rs10762474; hg19: chr10-73499561; COSMIC: COSV56448822; COSMIC: COSV56448822;