rs397517314

chr10-71690557-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_022124.6(CDH23):c.2149A>G(p.Thr717Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.581

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07591164).
• BP6: Variant 10-71690557-A-G is Benign according to our data. Variant chr10-71690557-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 45888.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.2149A>G	p.Thr717Ala	missense_variant	20/70	ENST00000224721.12
CDH23	NM_001171930.2	c.2149A>G	p.Thr717Ala	missense_variant	20/32
CDH23	NM_001171931.2	c.2149A>G	p.Thr717Ala	missense_variant	20/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.2149A>G	p.Thr717Ala	missense_variant	20/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454692 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 14, 2011

Thr717Ala in exon 20 of CDH23: This variant is not expected to have clinical sig nificance because computational analyses (PolyPhen2, SIFT, AlignGVGD) do not sug gest a high likelihood of impact to the protein, primarily based upon a lack of conservation across species including mammals. Of note, orangutan, macaque, and rhesus have analanine (Ala) at this position despite high nearby amino acid cons ervation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	9.4
Dann	Benign	0.49
DEOGEN2	Benign	0.0033	T;T;T;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.26	T;T;T;T;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.076	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.36	T;T;.;T;T;.
Polyphen		0.0	.;.;B;.;.;.
Vest4		0.23
MutPred		0.45		Gain of catalytic residue at Q718 (P = 0.07);Gain of catalytic residue at Q718 (P = 0.07);Gain of catalytic residue at Q718 (P = 0.07);Gain of catalytic residue at Q718 (P = 0.07);Gain of catalytic residue at Q718 (P = 0.07);Gain of catalytic residue at Q718 (P = 0.07);
MVP		0.34
ClinPred		0.065	T
GERP RS		-6.3
Varity_R		0.12
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs397517314; hg19: chr10-73450314;