chr2-135822071-A-G

Position:

chr2-135822071-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_002299.4(LCT):c.935T>C(p.Ile312Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,606,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

LCT
NM_002299.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.72

Variant links:

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]

LCT links:

LCT-AS1 (HGNC:40337): (LCT antisense RNA 1)

LCT-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31454617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LCT	NM_002299.4 linkuse as main transcript	c.935T>C	p.Ile312Thr	missense_variant	5/17	ENST00000264162.7
LCT-AS1	NR_045486.1 linkuse as main transcript	n.846A>G		non_coding_transcript_exon_variant	2/2
LCT	XM_017004088.3 linkuse as main transcript	c.935T>C	p.Ile312Thr	missense_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7 linkuse as main transcript	c.935T>C	p.Ile312Thr	missense_variant	5/17	1	NM_002299.4	P1
LCT-AS1	ENST00000437007.1 linkuse as main transcript	n.846A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251424

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1453976

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724010

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000530

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000576

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.935T>C (p.I312T) alteration is located in exon 5 (coding exon 5) of the LCT gene. This alteration results from a T to C substitution at nucleotide position 935, causing the isoleucine (I) at amino acid position 312 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2021

This sequence change replaces isoleucine with threonine at codon 312 of the LCT protein (p.Ile312Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals with LCT-related conditions. This variant is present in population databases (rs749365569, ExAC 0.1%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.075

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

M_CAP

Benign

0.0073

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.87

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.82

REVEL

Benign

0.17

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

0.56

Vest4

0.82

MutPred

0.66

Loss of stability (P = 0.0145);

MVP

0.61

MPC

0.39

ClinPred

0.18

GERP RS

4.3

Varity_R

0.15

gMVP

0.54

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over