rs374955091

Variant names:

• chr10-71690579-G-A
• rs374955091
• NM_022124.6:c.2171G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71690579-G-A
• chr10-71690579-G-C
• chr10-71690579-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022124.6(CDH23):​c.2171G>A​(p.Arg724His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,588,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R724G) has been classified as Uncertain significance. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.41
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029466987).
• BP6: Variant 10-71690579-G-A is Benign according to our data. Variant chr10-71690579-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162893.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000723 (11/152172) while in subpopulation SAS AF = 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.2171G>A	p.Arg724His	missense	Exon 20 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.2171G>A	p.Arg724His	missense	Exon 20 of 32	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.2171G>A	p.Arg724His	missense	Exon 20 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2171G>A	p.Arg724His	missense	Exon 20 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.2171G>A	p.Arg724His	missense	Exon 20 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.2171G>A	p.Arg724His	missense	Exon 20 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152054 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000296 AC: 62 AN: 209410 AF XY: 0.000382

Gnomad AFR exome AF: 0.0000844

Gnomad AMR exome AF: 0.0000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000160 AC: 230 AN: 1435872 Hom.: 0 Cov.: 29 AF XY: 0.000216 AC XY: 154 AN XY: 712048

African (AFR) AF: 0.0000608 AC: 2 AN: 32902

American (AMR) AF: 0.0000237 AC: 1 AN: 42264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25566

East Asian (EAS) AF: 0.00 AC: 0 AN: 38426

South Asian (SAS) AF: 0.00179 AC: 147 AN: 81898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000683 AC: 75 AN: 1097902

Other (OTH) AF: 0.0000842 AC: 5 AN: 59400

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74394

African (AFR) AF: 0.0000241 AC: 1 AN: 41514

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000526 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000349 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.4
PrimateAI	Uncertain	0.72	T
REVEL	Uncertain	0.29
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.94
ClinPred		0.34	T
GERP RS		5.1
Varity_R		0.65
gMVP		0.46
Mutation Taster		=57/43	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: rs374955091; hg19: chr10-73450336; COSMIC: COSV54943559;