10-71803045-T-G

Position:

• chr10-71803045-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. L2544L) has been classified as Likely benign.

• 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

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-71803045-T-G is Benign according to our data. Variant chr10-71803045-T-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7630T>G	p.Leu2544Val	missense_variant	54/70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.910T>G	p.Leu304Val	missense_variant	7/23		NP_001165404.1
CDH23	NM_001171934.1	c.910T>G	p.Leu304Val	missense_variant	7/22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7630T>G	p.Leu2544Val	missense_variant	54/70	5	NM_022124.6	ENSP00000224721	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.071	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.99	.;N;.;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.88	.;.;.;N
REVEL	Benign	0.025
Sift	Benign	0.37	.;.;.;T
Sift4G	Benign	1.0	T;.;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.085
MutPred		0.56		Gain of glycosylation at T2545 (P = 0.1309);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs114819374; hg19: chr10-73562802;