chr2-135798089-T-C

Position:

chr2-135798089-T-C

Variant summary

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

The NM_002299.4(LCT):c.4916A>G(p.Asn1639Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,611,080 control chromosomes in the GnomAD database, including 423,167 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 Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 28339 hom., cov: 30)

Exomes 𝑓: 0.72 ( 394828 hom. )

Consequence

LCT
NM_002299.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.919

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=2.1393369E-6).

BP6

Variant 2-135798089-T-C is Benign according to our data. Variant chr2-135798089-T-C is described in ClinVar as [Benign]. Clinvar id is 331168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135798089-T-C is described in Lovd as [Likely_pathogenic]. Variant chr2-135798089-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.732 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.4916A>G	p.Asn1639Ser	missense_variant	13/17	ENST00000264162.7
LCT	XM_017004088.3 linkuse as main transcript	c.4916A>G	p.Asn1639Ser	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7 linkuse as main transcript	c.4916A>G	p.Asn1639Ser	missense_variant	13/17	1	NM_002299.4	P1
LCT	ENST00000452974.1 linkuse as main transcript	c.3009A>G	p.Gln1003=	synonymous_variant, NMD_transcript_variant	6/7	1

Frequencies

GnomAD3 genomes

AF:

0.586

AC:

88941

AN:

151840

Hom.:

28336

Cov.:

show subpopulations

Gnomad AFR

AF:

0.396

Gnomad AMI

AF:

0.776

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.371

Gnomad EAS

AF:

0.473

Gnomad SAS

AF:

0.437

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.737

Gnomad OTH

AF:

0.515

GnomAD3 exomes

AF:

0.605

AC:

152212

AN:

251436

Hom.:

49834

AF XY:

0.604

AC XY:

82098

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.392

Gnomad AMR exome

AF:

0.502

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.477

Gnomad SAS exome

AF:

0.455

Gnomad FIN exome

AF:

0.734

Gnomad NFE exome

AF:

0.726

Gnomad OTH exome

AF:

0.588

GnomAD4 exome

AF:

0.720

AC:

1050134

AN:

1459122

Hom.:

394828

Cov.:

AF XY:

0.709

AC XY:

515018

AN XY:

726126

show subpopulations

Gnomad4 AFR exome

AF:

0.369

Gnomad4 AMR exome

AF:

0.497

Gnomad4 ASJ exome

AF:

0.371

Gnomad4 EAS exome

AF:

0.498

Gnomad4 SAS exome

AF:

0.464

Gnomad4 FIN exome

AF:

0.732

Gnomad4 NFE exome

AF:

0.780

Gnomad4 OTH exome

AF:

0.656

GnomAD4 genome

AF:

0.586

AC:

88972

AN:

151958

Hom.:

28339

Cov.:

AF XY:

0.576

AC XY:

42816

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.396

Gnomad4 AMR

AF:

0.460

Gnomad4 ASJ

AF:

0.371

Gnomad4 EAS

AF:

0.472

Gnomad4 SAS

AF:

0.438

Gnomad4 FIN

AF:

0.735

Gnomad4 NFE

AF:

0.737

Gnomad4 OTH

AF:

0.510

Alfa

AF:

0.649

Hom.:

56735

Bravo

AF:

0.561

TwinsUK

AF:

0.784

AC:

2907

ALSPAC

AF:

0.799

AC:

3081

ESP6500AA

AF:

0.407

AC:

1794

ESP6500EA

AF:

0.726

AC:

6240

ExAC

AF:

0.606

AC:

73536

Asia WGS

AF:

0.454

AC:

1580

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Congenital lactase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lactose intolerance

Benign:1

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

0.059

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.32

DANN

Benign

0.74

DEOGEN2

Benign

0.20

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.53

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.10

REVEL

Benign

0.12

Sift

Benign

0.13

Sift4G

Benign

0.49

Polyphen

0.013

Vest4

0.056

MPC

0.52

ClinPred

0.011

GERP RS

-8.9

Varity_R

0.044

gMVP

0.64

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