16-89193490-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004933.3(CDH15):c.1876C>T(p.Leu626Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,611,684 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 27)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: CDH15 NM_004933.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.539

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038324296).
• BP6: Variant 16-89193490-C-T is Benign according to our data. Variant chr16-89193490-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00498 (755/151654) while in subpopulation AFR AF= 0.0175 (721/41280). AF 95% confidence interval is 0.0164. There are 6 homozygotes in gnomad4. There are 355 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAd at 754 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH15	NM_004933.3	c.1876C>T	p.Leu626Phe	missense_variant	12/14	ENST00000289746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH15	ENST00000289746.3	c.1876C>T	p.Leu626Phe	missense_variant	12/14	1	NM_004933.3	P1

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 754 AN: 151540 Hom.: 6 Cov.: 27

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00435

GnomAD3 exomes AF: 0.00141 AC: 350 AN: 247840 Hom.: 5 AF XY: 0.000956 AC XY: 129 AN XY: 134968

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000521 AC: 760 AN: 1460030 Hom.: 8 Cov.: 37 AF XY: 0.000421 AC XY: 306 AN XY: 726276

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00498 AC: 755 AN: 151654 Hom.: 6 Cov.: 27 AF XY: 0.00479 AC XY: 355 AN XY: 74078

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00430

Alfa AF: 0.000882 Hom.: 1

Bravo AF: 0.00598

ESP6500AA AF: 0.0167 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00184 AC: 222

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	7.0
Dann	Benign	0.97
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.11
Sift	Benign	0.073	T
Sift4G	Benign	0.29	T
Polyphen		0.87	P
Vest4		0.12
MVP		0.54
MPC		0.033
ClinPred		0.0036	T
GERP RS		-1.0
Varity_R		0.091
gMVP		0.35

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: rs78261372; hg19: chr16-89259898;