2-135803987-G-C

Position:

• chr2-135803987-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000264162.7(LCT):​c.4606C>G​(p.Leu1536Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 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. L1536L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LCT ENST00000264162.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.196

Genes affected

LCT (HGNC:6530): (lactase) The protein encoded by this gene belongs to the glycosyl hydrolase 1 family of proteins. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme is integral to the plasma membrane and has both phlorizin hydrolase activity and lactase activity. Mutations in this gene are associated with congenital lactase deficiency. Polymorphisms in this gene are associated with lactase persistence, in which intestinal lactase activity persists at childhood levels into adulthood. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LCT. . Gene score misZ 3.1554 (greater than the threshold 3.09). Trascript score misZ 4.9736 (greater than threshold 3.09). GenCC has associacion of gene with congenital lactase deficiency.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCT	NM_002299.4	c.4606C>G	p.Leu1536Val	missense_variant	11/17	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3	c.4606C>G	p.Leu1536Val	missense_variant	11/15		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.4606C>G	p.Leu1536Val	missense_variant	11/17	1	NM_002299.4	ENSP00000264162.2
LCT	ENST00000452974.1	n.2902C>G		non_coding_transcript_exon_variant	5/7	1		ENSP00000391231.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0063	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.085
Sift	Benign	0.053	T
Sift4G	Uncertain	0.031	D
Polyphen		0.45	B
Vest4		0.38
MutPred		0.75		Gain of MoRF binding (P = 0.2089);
MVP		0.59
MPC		0.70
ClinPred		0.50	D
GERP RS		2.8
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2304371; hg19: chr2-136561557;