16-89171833-T-A

Position:

• chr16-89171833-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004933.3(CDH15):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH15 NM_004933.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

Genes affected

CDH15 (HGNC:1754): (cadherin 15) This gene is a member of the cadherin superfamily of genes, encoding calcium-dependent intercellular adhesion glycoproteins. Cadherins consist of an extracellular domain containing 5 cadherin domains, a transmembrane region, and a conserved cytoplasmic domain. Transcripts from this particular cadherin are expressed in myoblasts and upregulated in myotubule-forming cells. The protein is thought to be essential for the control of morphogenetic processes, specifically myogenesis, and may provide a trigger for terminal muscle cell differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH15	NM_004933.3	c.2T>A	p.Met1?	start_lost	1/14	ENST00000289746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH15	ENST00000289746.3	c.2T>A	p.Met1?	start_lost	1/14	1	NM_004933.3	P1
CDH15	ENST00000521087.5	n.67T>A		non_coding_transcript_exon_variant	1/3	5
CDH15	ENST00000524089.1	n.67T>A		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406174 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 695338

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2017

The c.2 T>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.2 T>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if a protein is produced using an alternative Methionine initiator codon. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		0.93	P
Vest4		0.83
MutPred		0.87		Loss of stability (P = 0.0066);
MVP		0.81
ClinPred		0.71	D
GERP RS		2.8
Varity_R		0.92
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs1257048139; hg19: chr16-89238241;