rs1469134854

Variant names:

• chr16-89192267-C-A
• rs1469134854
• NM_004933.3:c.1678C>A
• CDH15 p.Leu560Met

Your query was ambiguous. Multiple possible variants found:

• chr16-89192267-C-A
• chr16-89192267-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004933.3(CDH15):​c.1678C>A​(p.Leu560Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,378,624 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L560L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CDH15 NM_004933.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.425
• Publications: 0 publications found

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]

CDH15 Gene-Disease associations (from GenCC):

• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal dominant 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004933.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH15	NM_004933.3	MANE Select	c.1678C>A	p.Leu560Met	missense	Exon 11 of 14	NP_004924.1	P55291

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH15	ENST00000289746.3	TSL:1 MANE Select	c.1678C>A	p.Leu560Met	missense	Exon 11 of 14	ENSP00000289746.2	P55291
	CDH15	ENST00000967215.1		c.1678C>A	p.Leu560Met	missense	Exon 11 of 14	ENSP00000637274.1
	CDH15	ENST00000859655.1		c.1528C>A	p.Leu510Met	missense	Exon 11 of 14	ENSP00000529714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1378624 Hom.: 0 Cov.: 33 AF XY: 0.00000294 AC XY: 2 AN XY: 680164

African (AFR) AF: 0.00 AC: 0 AN: 31140

American (AMR) AF: 0.00 AC: 0 AN: 35536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25034

East Asian (EAS) AF: 0.00 AC: 0 AN: 35486

South Asian (SAS) AF: 0.00 AC: 0 AN: 78936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077250

Other (OTH) AF: 0.00 AC: 0 AN: 57540

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.42
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Varity_R		0.12
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1469134854;

hg19: chr16-89258675;