rs377118941

Variant names:

• chr10-71815239-C-T
• rs377118941
• NM_022124.6:c.10026C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-71815239-C-T
• chr10-71815239-C-A
• chr10-71815239-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_022124.6(CDH23):​c.10026C>T​(p.Asp3342Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,591,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10
• Conservation: PhyloP100: -0.555
• Publications: 1 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
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-71815239-C-T is Benign according to our data. Variant chr10-71815239-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178317.
• BP7: Synonymous conserved (PhyloP=-0.555 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00164 (250/152392) while in subpopulation AFR AF = 0.00529 (220/41594). AF 95% confidence interval is 0.00472. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.10026C>T	p.Asp3342Asp	synonymous	Exon 70 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.3306C>T	p.Asp1102Asp	synonymous	Exon 23 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.3201C>T	p.Asp1067Asp	synonymous	Exon 22 of 22	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.10026C>T	p.Asp3342Asp	synonymous	Exon 70 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.3457C>T		non_coding_transcript_exon	Exon 21 of 21
	CDH23	ENST00000642965.1		n.*3869C>T		non_coding_transcript_exon	Exon 25 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152274 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000402 AC: 95 AN: 236352 AF XY: 0.000233

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000565

Gnomad OTH exome AF: 0.000522

GnomAD4 exome AF: 0.000186 AC: 267 AN: 1439214 Hom.: 1 Cov.: 31 AF XY: 0.000159 AC XY: 113 AN XY: 711816

African (AFR) AF: 0.00485 AC: 160 AN: 33012

American (AMR) AF: 0.000774 AC: 34 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25222

East Asian (EAS) AF: 0.000255 AC: 10 AN: 39248

South Asian (SAS) AF: 0.00 AC: 0 AN: 84618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51842

Middle Eastern (MID) AF: 0.000704 AC: 4 AN: 5682

European-Non Finnish (NFE) AF: 0.0000237 AC: 26 AN: 1096332

Other (OTH) AF: 0.000556 AC: 33 AN: 59334

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152392 Hom.: 0 Cov.: 34 AF XY: 0.00162 AC XY: 121 AN XY: 74526

African (AFR) AF: 0.00529 AC: 220 AN: 41594

American (AMR) AF: 0.00131 AC: 20 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00193

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	CDH23-related disorder (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Atypical Gaucher Disease (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	1	-	Hearing loss, autosomal recessive (1)
-	-	1	Metachromatic leukodystrophy (1)
-	1	-	Retinitis pigmentosa-deafness syndrome (1)
-	-	1	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.31
DANN	Benign	0.90
PhyloP100		-0.56
Mutation Taster		=94/6	polymorphism

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: rs377118941; hg19: chr10-73574996; COSMIC: COSV56474074; COSMIC: COSV56474074;