rs147397532

chr16-89193908-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004933.3(CDH15):c.2146A>G(p.Asn716Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,611,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: CDH15 NM_004933.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.430

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019061387).
• BP6: Variant 16-89193908-A-G is Benign according to our data. Variant chr16-89193908-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210627.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH15	NM_004933.3	c.2146A>G	p.Asn716Asp	missense_variant	13/14	ENST00000289746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH15	ENST00000289746.3	c.2146A>G	p.Asn716Asp	missense_variant	13/14	1	NM_004933.3	P1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151832 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000792 AC: 19 AN: 239968 Hom.: 0 AF XY: 0.0000532 AC XY: 7 AN XY: 131670

Gnomad AFR exome AF: 0.000607

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000850

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1459822 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14 AN XY: 726216

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000179

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: 0.00000989

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151950 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74252

Gnomad4 AFR AF: 0.000966

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000378

ESP6500AA AF: 0.000690 AC: 3

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000133 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 2022	The c.2146A>G (p.N716D) alteration is located in exon 13 (coding exon 13) of the CDH15 gene. This alteration results from a A to G substitution at nucleotide position 2146, causing the asparagine (N) at amino acid position 716 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	17
Dann	Benign	0.60
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Benign	0.81	T
Sift4G	Benign	0.34	T
Polyphen		0.023	B
Vest4		0.20
MVP		0.56
MPC		0.13
ClinPred		0.013	T
GERP RS		0.40
Varity_R		0.12
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147397532; hg19: chr16-89260316;