rs111033488

Variant names:

• chr10-71730508-G-A
• rs111033488
• NM_022124.6:c.3619G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71730508-G-A
• chr10-71730508-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_022124.6(CDH23):​c.3619G>A​(p.Val1207Met) variant causes a missense change. The variant allele was found at a frequency of 0.00256 in 1,613,920 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1207A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.11
• Publications: 6 publications found

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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075572133).
• BP6: Variant 10-71730508-G-A is Benign according to our data. Variant chr10-71730508-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45925.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.3619G>A	p.Val1207Met	missense	Exon 31 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3619G>A	p.Val1207Met	missense	Exon 31 of 32	NP_001165401.1
	C10orf105	NM_001168390.2		c.-6+7220C>T		intron	N/A	NP_001161862.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3619G>A	p.Val1207Met	missense	Exon 31 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.3619G>A	p.Val1207Met	missense	Exon 31 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.3616G>A	p.Val1206Met	missense	Exon 31 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2025 AN: 152194 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00358 AC: 891 AN: 248972 AF XY: 0.00275

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00144 AC: 2105 AN: 1461608 Hom.: 47 Cov.: 31 AF XY: 0.00123 AC XY: 897 AN XY: 727088

African (AFR) AF: 0.0527 AC: 1765 AN: 33478

American (AMR) AF: 0.00201 AC: 90 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5734

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111848

Other (OTH) AF: 0.00298 AC: 180 AN: 60366

GnomAD4 genome AF: 0.0133 AC: 2030 AN: 152312 Hom.: 50 Cov.: 33 AF XY: 0.0130 AC XY: 969 AN XY: 74482

African (AFR) AF: 0.0472 AC: 1963 AN: 41568

American (AMR) AF: 0.00307 AC: 47 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00305 Hom.: 29

Bravo AF: 0.0153

ESP6500AA AF: 0.0453 AC: 183

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00420 AC: 508

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.1
PrimateAI	Benign	0.40	T
REVEL	Benign	0.11
Sift4G	Uncertain	0.023	D
Polyphen		0.15	B
Vest4		0.41
MVP		0.59
ClinPred		0.033	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.24
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033488; hg19: chr10-73490265; COSMIC: COSV56476549;