rs148149598

chr10-71800736-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_022124.6(CDH23):c.7463G>A(p.Arg2488His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,864 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2488C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00082 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.51

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02180326).
• BP6: Variant 10-71800736-G-A is Benign according to our data. Variant chr10-71800736-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 162941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.7463G>A	p.Arg2488His	missense_variant	53/70	ENST00000224721.12
CDH23	NM_001171933.1	c.743G>A	p.Arg248His	missense_variant	6/23
CDH23	NM_001171934.1	c.743G>A	p.Arg248His	missense_variant	6/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.7463G>A	p.Arg2488His	missense_variant	53/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000796 AC: 121 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 41 AN: 249176 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135188

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461652 Hom.: 0 Cov.: 30 AF XY: 0.000109 AC XY: 79 AN XY: 727092

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74414

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0207 Hom.: 2232

Bravo AF: 0.000812

ESP6500AA AF: 0.00251 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000223 AC: 27

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 16, 2015

p.Arg2488His in exon 53 of CDH23: This variant is not expected to have clinical significance because it has been identified in 0.2% (18/9494) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.orgdb SNP rs148149598). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.027	T;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.95	.;P;.;.
Vest4		0.50
MVP		0.73
MPC		0.68
ClinPred		0.055	T
GERP RS		5.5
Varity_R		0.38
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs148149598; hg19: chr10-73560493;