rs111033288

Variant names:

• chr10-71510134-G-A
• rs111033288
• NM_022124.6:c.198G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_022124.6(CDH23):​c.198G>A​(p.Val66Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,058 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (63 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.00100
• Publications: 3 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]

CDH23-AS1 (HGNC:31433): (CDH23 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-71510134-G-A is Benign according to our data. Variant chr10-71510134-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.001 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00177 (270/152362) while in subpopulation SAS AF = 0.0224 (108/4828). AF 95% confidence interval is 0.019. There are 2 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.198G>A	p.Val66Val	synonymous	Exon 4 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.198G>A	p.Val66Val	synonymous	Exon 4 of 32	NP_001165401.1
	CDH23	NM_001171931.2		c.198G>A	p.Val66Val	synonymous	Exon 4 of 26	NP_001165402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.198G>A	p.Val66Val	synonymous	Exon 4 of 70	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.198G>A	p.Val66Val	synonymous	Exon 4 of 32	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.198G>A	p.Val66Val	synonymous	Exon 4 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152244 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00450 AC: 1123 AN: 249288 AF XY: 0.00586

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00288 AC: 4217 AN: 1461696 Hom.: 63 Cov.: 31 AF XY: 0.00374 AC XY: 2722 AN XY: 727130

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0265 AC: 2290 AN: 86256

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53396

Middle Eastern (MID) AF: 0.0140 AC: 81 AN: 5768

European-Non Finnish (NFE) AF: 0.00134 AC: 1490 AN: 1111862

Other (OTH) AF: 0.00321 AC: 194 AN: 60374

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152362 Hom.: 2 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74512

African (AFR) AF: 0.000313 AC: 13 AN: 41586

American (AMR) AF: 0.000849 AC: 13 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 68042

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00332

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.7
DANN	Benign	0.80
PhyloP100		0.0010
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs111033288; hg19: chr10-73269891; COSMIC: COSV107305332; COSMIC: COSV107305332;