rs11818398

Variant names:

• chr10-71810577-G-A
• rs11818398
• NM_022124.6:c.9077+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71810577-G-A
• chr10-71810577-G-T

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.9077+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,612,384 control chromosomes in the GnomAD database, including 27,803 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1978 hom., cov: 31)
  • Exomes 𝑓: 0.18 (25825 hom.)
• Consequence: CDH23 NM_022124.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004291
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.703
• Publications: 10 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
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902446 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-71810577-G-A is Benign according to our data. Variant chr10-71810577-G-A is described in ClinVar as Benign. ClinVar VariationId is 46068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 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.9077+8G>A		splice_region intron	N/A	NP_071407.4
	CDH23	NM_001171933.1		c.2357+8G>A		splice_region intron	N/A	NP_001165404.1	Q9H251-7
	CDH23	NM_001171934.1		c.2357+8G>A		splice_region intron	N/A	NP_001165405.1	Q9H251-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9077+8G>A		splice_region intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000475158.1	TSL:1	n.2613+8G>A		splice_region intron	N/A
	CDH23	ENST00000642965.1		n.*2920+8G>A		splice_region intron	N/A	ENSP00000495222.1	A0A2R8Y6D5

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23149 AN: 152016 Hom.: 1978 Cov.: 31

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.169 AC: 41912 AN: 248730 AF XY: 0.168

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.185 AC: 269520 AN: 1460250 Hom.: 25825 Cov.: 32 AF XY: 0.183 AC XY: 132584 AN XY: 726452

African (AFR) AF: 0.0761 AC: 2548 AN: 33464

American (AMR) AF: 0.119 AC: 5337 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4451 AN: 26118

East Asian (EAS) AF: 0.275 AC: 10911 AN: 39668

South Asian (SAS) AF: 0.129 AC: 11112 AN: 86230

European-Finnish (FIN) AF: 0.219 AC: 11675 AN: 53374

Middle Eastern (MID) AF: 0.125 AC: 723 AN: 5766

European-Non Finnish (NFE) AF: 0.191 AC: 212131 AN: 1110626

Other (OTH) AF: 0.176 AC: 10632 AN: 60306

GnomAD4 genome AF: 0.152 AC: 23149 AN: 152134 Hom.: 1978 Cov.: 31 AF XY: 0.154 AC XY: 11423 AN XY: 74390

African (AFR) AF: 0.0787 AC: 3268 AN: 41526

American (AMR) AF: 0.145 AC: 2217 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3472

East Asian (EAS) AF: 0.248 AC: 1280 AN: 5158

South Asian (SAS) AF: 0.127 AC: 611 AN: 4820

European-Finnish (FIN) AF: 0.223 AC: 2364 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12334 AN: 67954

Other (OTH) AF: 0.156 AC: 329 AN: 2106

Alfa AF: 0.167 Hom.: 964

Bravo AF: 0.143

Asia WGS AF: 0.135 AC: 472 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 12 (2)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 1D (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.46
PhyloP100		0.70
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0
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: rs11818398; hg19: chr10-73570334; COSMIC: COSV56452798;