16-89191733-C-T

Position:

• chr16-89191733-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000289746.3(CDH15):​c.1454C>T​(p.Pro485Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,603,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CDH15 ENST00000289746.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.396

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027048051).
• BP6: Variant 16-89191733-C-T is Benign according to our data. Variant chr16-89191733-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 434636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89191733-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH15	NM_004933.3	c.1454C>T	p.Pro485Leu	missense_variant	10/14	ENST00000289746.3	NP_004924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH15	ENST00000289746.3	c.1454C>T	p.Pro485Leu	missense_variant	10/14	1	NM_004933.3	ENSP00000289746	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000195 AC: 43 AN: 220560 Hom.: 0 AF XY: 0.000163 AC XY: 20 AN XY: 123024

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.000475

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.0000578

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.000306 AC: 444 AN: 1451258 Hom.: 0 Cov.: 34 AF XY: 0.000295 AC XY: 213 AN XY: 722164

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000472

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000293

Gnomad4 OTH exome AF: 0.000582

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74426

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.000295

ExAC AF: 0.000171 AC: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.68
DEOGEN2	Benign	0.056	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.076
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.37
MPC		0.031
ClinPred		0.015	T
GERP RS		-2.6
Varity_R		0.022
gMVP		0.49

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: rs533094369; hg19: chr16-89258141;