2-135788340-G-T

Position:

chr2-135788340-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002299.4(LCT):c.5768C>A(p.Pro1923Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,612,928 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1923L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 55 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 50 hom. )

Consequence

LCT
NM_002299.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.695

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.0015354455).

BP6

Variant 2-135788340-G-T is Benign according to our data. Variant chr2-135788340-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 331162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4 linkuse as main transcript	c.5768C>A	p.Pro1923Gln	missense_variant	17/17	ENST00000264162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7 linkuse as main transcript	c.5768C>A	p.Pro1923Gln	missense_variant	17/17	1	NM_002299.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2410

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00389

AC:

978

AN:

251284

Hom.:

AF XY:

0.00273

AC XY:

371

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0539

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00149

AC:

2172

AN:

1460682

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

949

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.0536

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.00316

GnomAD4 genome

AF:

0.0158

AC:

2412

AN:

152246

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1095

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0549

Gnomad4 AMR

AF:

0.00602

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.000761

Hom.:

Bravo

AF:

0.0182

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0517

AC:

228

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00475

AC:

577

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Lactose intolerance

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

LCT-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital lactase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.053

DANN

Benign

0.58

DEOGEN2

Benign

0.27

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

0.28

REVEL

Benign

0.0070

Sift

Benign

0.24

Sift4G

Benign

0.20

Polyphen

0.0050

Vest4

0.079

MVP

0.092

MPC

0.58

ClinPred

0.0058

GERP RS

-4.3

Varity_R

0.031

gMVP

0.31

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