chr10-71690449-C-G

Variant names:

• chr10-71690449-C-G
• rs2290024
• NM_022124.6:c.2060-19C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.2060-19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,565,888 control chromosomes in the GnomAD database, including 2,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (288 hom., cov: 33)
  • Exomes 𝑓: 0.024 (2277 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.473
• Publications: 4 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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-71690449-C-G is Benign according to our data. Variant chr10-71690449-C-G is described in ClinVar as Benign. ClinVar VariationId is 136700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.246 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.2060-19C>G		intron	N/A	NP_071407.4
	CDH23	NM_001171930.2		c.2060-19C>G		intron	N/A	NP_001165401.1
	CDH23	NM_001171931.2		c.2060-19C>G		intron	N/A	NP_001165402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2060-19C>G		intron	N/A	ENSP00000224721.9
	CDH23	ENST00000616684.4	TSL:5	c.2060-19C>G		intron	N/A	ENSP00000482036.2
	CDH23	ENST00000398809.9	TSL:5	c.2060-19C>G		intron	N/A	ENSP00000381789.5

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5063 AN: 152192 Hom.: 279 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0596 AC: 11549 AN: 193688 AF XY: 0.0535

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.255

Gnomad FIN exome AF: 0.00939

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0240 AC: 33938 AN: 1413578 Hom.: 2277 Cov.: 28 AF XY: 0.0240 AC XY: 16768 AN XY: 700008

African (AFR) AF: 0.0179 AC: 581 AN: 32376

American (AMR) AF: 0.178 AC: 7055 AN: 39714

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 416 AN: 25310

East Asian (EAS) AF: 0.263 AC: 9834 AN: 37454

South Asian (SAS) AF: 0.0394 AC: 3175 AN: 80666

European-Finnish (FIN) AF: 0.00955 AC: 487 AN: 51018

Middle Eastern (MID) AF: 0.0475 AC: 256 AN: 5384

European-Non Finnish (NFE) AF: 0.00943 AC: 10210 AN: 1083084

Other (OTH) AF: 0.0328 AC: 1924 AN: 58572

GnomAD4 genome AF: 0.0335 AC: 5102 AN: 152310 Hom.: 288 Cov.: 33 AF XY: 0.0360 AC XY: 2679 AN XY: 74472

African (AFR) AF: 0.0204 AC: 847 AN: 41572

American (AMR) AF: 0.114 AC: 1742 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1331 AN: 5174

South Asian (SAS) AF: 0.0335 AC: 162 AN: 4830

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 751 AN: 68020

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.00951 Hom.: 4

Bravo AF: 0.0441

Asia WGS AF: 0.112 AC: 389 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.50
DANN	Benign	0.60
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs2290024; hg19: chr10-73450206; COSMIC: COSV54951656;