NM_022124.6:c.3397G>T

Variant names:

• chr10-71724072-G-T
• rs111033509
• NM_022124.6:c.3397G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022124.6(CDH23):​c.3397G>T​(p.Glu1133*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E1133E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH23 NM_022124.6 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.24
• 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]

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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-71724072-G-T is Pathogenic according to our data. Variant chr10-71724072-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2680515.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3397G>T	p.Glu1133*	stop_gained	Exon 29 of 70	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.3397G>T	p.Glu1133*	stop_gained	Exon 29 of 32		NP_001165401.1
C10orf105	NM_001168390.2	c.-5-7730C>A		intron_variant	Intron 1 of 1		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3397G>T	p.Glu1133*	stop_gained	Exon 29 of 70	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 695254

African (AFR) AF: 0.00 AC: 0 AN: 32098

American (AMR) AF: 0.00 AC: 0 AN: 36752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36558

South Asian (SAS) AF: 0.00 AC: 0 AN: 79624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083856

Other (OTH) AF: 0.00 AC: 0 AN: 58420

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary adenoma 5, multiple types Pathogenic:1

Nov 16, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.2
Vest4		0.88
GERP RS		4.9
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111033509; hg19: chr10-73483829; COSMIC: COSV99823891;