chr2-181539124-G-T

Variant names:

• chr2-181539124-G-T
• rs10180793
• NM_201548.5:c.1506C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201548.5(CERKL):​c.1506C>A​(p.Asp502Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D502D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CERKL NM_201548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.749
• Publications: 19 publications found

Genes affected

CERKL (HGNC:21699): (ceramide kinase like) This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

ITGA4 (HGNC:6140): (integrin subunit alpha 4) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 4 subunit. This subunit associates with a beta 1 or beta 7 subunit to form an integrin that may play a role in cell motility and migration. This integrin is a therapeutic target for the treatment of multiple sclerosis, Crohn's disease and inflammatory bowel disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17434138).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	NM_201548.5	MANE Select	c.1506C>A	p.Asp502Glu	missense	Exon 12 of 13	NP_963842.1
	CERKL	NM_001030311.3		c.1584C>A	p.Asp528Glu	missense	Exon 13 of 14	NP_001025482.1
	CERKL	NM_001160277.2		c.1452C>A	p.Asp484Glu	missense	Exon 12 of 13	NP_001153749.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.1506C>A	p.Asp502Glu	missense	Exon 12 of 13	ENSP00000386725.3
	CERKL	ENST00000339098.9	TSL:1	c.1584C>A	p.Asp528Glu	missense	Exon 13 of 14	ENSP00000341159.5
	CERKL	ENST00000374970.6	TSL:1	c.1299C>A	p.Asp433Glu	missense	Exon 10 of 11	ENSP00000364109.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.75
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.37	T
Polyphen		0.77	P
Vest4		0.33
MutPred		0.73		Loss of sheet (P = 0.0457)
MVP		0.23
MPC		0.18
ClinPred		0.45	T
GERP RS		0.14
Varity_R		0.072
gMVP		0.26
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs10180793; hg19: chr2-182403851;