rs114367774

Variant names:

• chr10-71439701-T-G
• rs114367774
• NM_022124.6:c.-5-126T>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.-5-126T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00619 in 672,498 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (90 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (32 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.464
• Publications: 0 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=-0.85).
• BP6: Variant 10-71439701-T-G is Benign according to our data. Variant chr10-71439701-T-G is described in ClinVar as [Benign]. Clinvar id is 1244165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.-5-126T>G		intron_variant	Intron 1 of 69	ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.-5-126T>G		intron_variant	Intron 1 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2948 AN: 152158 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.00231 AC: 1201 AN: 520222 Hom.: 32 AF XY: 0.00189 AC XY: 519 AN XY: 274764

African (AFR) AF: 0.0605 AC: 840 AN: 13892

American (AMR) AF: 0.00502 AC: 127 AN: 25284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15238

East Asian (EAS) AF: 0.00 AC: 0 AN: 31628

South Asian (SAS) AF: 0.000218 AC: 11 AN: 50356

European-Finnish (FIN) AF: 0.0000264 AC: 1 AN: 37920

Middle Eastern (MID) AF: 0.00427 AC: 16 AN: 3750

European-Non Finnish (NFE) AF: 0.000214 AC: 67 AN: 313476

Other (OTH) AF: 0.00485 AC: 139 AN: 28678

GnomAD4 genome AF: 0.0194 AC: 2961 AN: 152276 Hom.: 90 Cov.: 33 AF XY: 0.0187 AC XY: 1391 AN XY: 74460

African (AFR) AF: 0.0672 AC: 2791 AN: 41532

American (AMR) AF: 0.00791 AC: 121 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0178 Hom.: 8

Bravo AF: 0.0211

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.34
DANN	Benign	0.42
PhyloP100		-0.46
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	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: rs114367774; hg19: chr10-73199458;