10-71803045-T-G

Variant names:

• chr10-71803045-T-G
• rs114819374
• NM_022124.6:c.7630T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022124.6(CDH23):​c.7630T>G​(p.Leu2544Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 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. L2544F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.332
• 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, 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.7630T>G	p.Leu2544Val	missense	Exon 54 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.910T>G	p.Leu304Val	missense	Exon 7 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.910T>G	p.Leu304Val	missense	Exon 7 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.7630T>G	p.Leu2544Val	missense	Exon 54 of 70	ENSP00000224721.9
	CDH23	ENST00000398788.4	TSL:1	c.910T>G	p.Leu304Val	missense	Exon 7 of 23	ENSP00000381768.3
	CDH23	ENST00000619887.4	TSL:1	c.910T>G	p.Leu304Val	missense	Exon 7 of 22	ENSP00000478374.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460998 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 726634

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111294

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.64
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.99	N
PhyloP100		-0.33
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.025
Sift	Benign	0.37	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.085
MutPred		0.56		Gain of glycosylation at T2545 (P = 0.1309)
MVP		0.25
MPC		0.15
ClinPred		0.24	T
GERP RS		-3.2
Varity_R		0.041
gMVP		0.17
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.81		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs114819374; hg19: chr10-73562802;