10-71805854-G-C

Variant names:

• chr10-71805854-G-C
• rs397517354
• NM_022124.6:c.7921G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_022124.6(CDH23):​c.7921G>C​(p.Asp2641His) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2641G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.96

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-71805855-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3601604.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 10-71805854-G-C is Pathogenic according to our data. Variant chr10-71805854-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 46041.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.7921G>C	p.Asp2641His	missense_variant	Exon 56 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171933.1	c.1201G>C	p.Asp401His	missense_variant	Exon 9 of 23		NP_001165404.1
CDH23	NM_001171934.1	c.1201G>C	p.Asp401His	missense_variant	Exon 9 of 22		NP_001165405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.7921G>C	p.Asp2641His	missense_variant	Exon 56 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248358 AF XY: 0.00000742

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asp2641His variant in CDH23 has not been reported in the literature nor prev iously identified by our laboratory. This residue is conserved across species an d computational analyses (PolyPhen, SIFT) suggest that the Asp2641His variant ma y impact the protein. The presence of this variant in combination with a pathoge nic variant and in an individual with clinical features of Usher syndrome, incre ases the likelihood that the Asp2641His variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;D;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	4.5	.;H;.;.
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.0	.;.;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.95
MutPred		0.87		Loss of ubiquitination at K2640 (P = 0.077);Loss of ubiquitination at K2640 (P = 0.077);.;.;
MVP		0.93
MPC		0.69
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.57
gMVP		0.93
Mutation Taster		=11/89	disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs397517354; hg19: chr10-73565611;