rs201364852

chr10-71777872-G-Achr10-71777872-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_022124.6(CDH23):c.5038G>A(p.Val1680Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,740 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.21

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026540965).
• BP6: Variant 10-71777872-G-A is Benign according to our data. Variant chr10-71777872-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162917.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr10-71777872-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.5038G>A	p.Val1680Ile	missense_variant	39/70	ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.5038G>A	p.Val1680Ile	missense_variant	39/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000883 AC: 22 AN: 249278 Hom.: 0 AF XY: 0.0000814 AC XY: 11 AN XY: 135188

Gnomad AFR exome AF: 0.000642

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461690 Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35 AN XY: 727136

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74252

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000909 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000907 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH23 p.Val1680Ile variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs201364852) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine). The variant was also identified in control databases in 35 of 280646 chromosomes at a frequency of 0.000125 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 22 of 24270 chromosomes (freq: 0.000907), European (non-Finnish) in 9 of 128346 chromosomes (freq: 0.00007), Latino in 2 of 35374 chromosomes (freq: 0.000057), East Asian in 1 of 19532 chromosomes (freq: 0.000051), and South Asian in 1 of 30600 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, European (Finnish), or other populations. The p.Val1680 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing at the variant location. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 28, 2013

Val1680Ile in Exon 39 of CDH23: This variant is not expected to have clinical si gnificance because the valine (Val) residue at position 1680 is poorly conserved across species, with many vertebrate, mammalian and primate species (including chimpanzee, gorilla, and orangutan) having an isoleucine (Ile) at this position. In addition, it has been identified in 0.01% (1/8566) of European American chr omosomes and 0.05% (2/4382) of African American chromosomes from a broad populat ion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; db SNP rs201364852). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	13
Dann	Benign	0.84
DEOGEN2	Benign	0.0073	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.034	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.61	T;.
Polyphen		0.0	.;B
Vest4		0.058
MVP		0.47
ClinPred		0.017	T
GERP RS		3.4
Varity_R		0.024
gMVP		0.17

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: rs201364852; hg19: chr10-73537629; COSMIC: COSV105842396; COSMIC: COSV105842396;