rs140463385

Variant names:

• chr10-71814971-A-C
• rs140463385
• NM_022124.6:c.9758A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-71814971-A-C
• chr10-71814971-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022124.6(CDH23):​c.9758A>C​(p.Asp3253Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,611,996 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D3253D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (21 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 6.29
• Publications: 11 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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008310497).
• BP6: Variant 10-71814971-A-C is Benign according to our data. Variant chr10-71814971-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00459 (699/152354) while in subpopulation AFR AF = 0.0134 (557/41580). AF 95% confidence interval is 0.0125. There are 5 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.9758A>C	p.Asp3253Ala	missense	Exon 70 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.3038A>C	p.Asp1013Ala	missense	Exon 23 of 23	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.2933A>C	p.Asp978Ala	missense	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.9758A>C	p.Asp3253Ala	missense	Exon 70 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.3189A>C		non_coding_transcript_exon	Exon 21 of 21
	CDH23	ENST00000642965.1		n.*3601A>C		non_coding_transcript_exon	Exon 25 of 25	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152236 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00291 AC: 706 AN: 242992 AF XY: 0.00312

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00436

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.00388

GnomAD4 exome AF: 0.00146 AC: 2124 AN: 1459642 Hom.: 21 Cov.: 31 AF XY: 0.00167 AC XY: 1212 AN XY: 726004

African (AFR) AF: 0.0141 AC: 471 AN: 33464

American (AMR) AF: 0.00166 AC: 74 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00464 AC: 121 AN: 26086

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.0102 AC: 880 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.00764 AC: 44 AN: 5758

European-Non Finnish (NFE) AF: 0.000324 AC: 360 AN: 1111330

Other (OTH) AF: 0.00285 AC: 172 AN: 60282

GnomAD4 genome AF: 0.00459 AC: 699 AN: 152354 Hom.: 5 Cov.: 34 AF XY: 0.00464 AC XY: 346 AN XY: 74500

African (AFR) AF: 0.0134 AC: 557 AN: 41580

American (AMR) AF: 0.00294 AC: 45 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00163 Hom.: 4

Bravo AF: 0.00491

ESP6500AA AF: 0.00787 AC: 32

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00299 AC: 361

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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	Metachromatic leukodystrophy (1)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.81	L
PhyloP100		6.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.030	B
Vest4		0.15
MVP		0.88
MPC		0.18
ClinPred		0.026	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.41
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140463385; hg19: chr10-73574728;