rs1554856028

chr10-71690504-A-Cchr10-71690504-A-Gchr10-71690504-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_022124.6(CDH23):c.2096A>C(p.Asp699Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 10/17 in silico tools predict a damaging 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. D699V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.78

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-71690504-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.2096A>C	p.Asp699Ala	missense_variant	20/70	ENST00000224721.12
CDH23	NM_001171930.2	c.2096A>C	p.Asp699Ala	missense_variant	20/32
CDH23	NM_001171931.2	c.2096A>C	p.Asp699Ala	missense_variant	20/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2096A>C	p.Asp699Ala	missense_variant	20/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;D;.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	0.076	T;D;.;D;T;.
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.94
MutPred		0.94		Loss of disorder (P = 0.0789);Loss of disorder (P = 0.0789);Loss of disorder (P = 0.0789);Loss of disorder (P = 0.0789);Loss of disorder (P = 0.0789);Loss of disorder (P = 0.0789);
MVP		0.95
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-73450261;