rs121908937

Positions:

• chr2-135829593-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The ENST00000264162.7(LCT):​c.804G>C​(p.Gln268His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LCT ENST00000264162.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.30

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 4 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.
• PP5: Variant 2-135829593-C-G is Pathogenic according to our data. Variant chr2-135829593-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 6588.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-135829593-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCT	NM_002299.4	c.804G>C	p.Gln268His	missense_variant, splice_region_variant	3/17	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3	c.804G>C	p.Gln268His	missense_variant, splice_region_variant	3/15		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.804G>C	p.Gln268His	missense_variant, splice_region_variant	3/17	1	NM_002299.4	ENSP00000264162	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457934 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital lactase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.73		Loss of disorder (P = 0.1236);
MVP		0.64
MPC		0.81
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.42
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908937; hg19: chr2-136587163;