chr10-71815240-G-C

Variant names:

• chr10-71815240-G-C
• rs756425157
• NM_022124.6:c.10027G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.10027G>C​(p.Val3343Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,438,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3343M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20
• Publications: 6 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23131064).

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.10027G>C	p.Val3343Leu	missense	Exon 70 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.3307G>C	p.Val1103Leu	missense	Exon 23 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.3202G>C	p.Val1068Leu	missense	Exon 22 of 22	NP_001165405.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.10027G>C	p.Val3343Leu	missense	Exon 70 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.3307G>C	p.Val1103Leu	missense	Exon 23 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.3202G>C	p.Val1068Leu	missense	Exon 22 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235706 AF XY: 0.00000779

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000945

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438592 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 711436

African (AFR) AF: 0.00 AC: 0 AN: 32988

American (AMR) AF: 0.00 AC: 0 AN: 43902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25196

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 84544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1095946

Other (OTH) AF: 0.00 AC: 0 AN: 59292

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000368 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.052
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.036	D
Polyphen		0.46	P
Vest4		0.36
MutPred		0.24		Gain of disorder (P = 0.051)
MVP		0.86
MPC		0.14
ClinPred		0.40	T
GERP RS		5.4
Varity_R		0.082
gMVP		0.34
Mutation Taster		=91/9	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: rs756425157; hg19: chr10-73574997;