chr2-135833176-C-T

Position:

chr2-135833176-C-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.655G>A(p.Val219Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,612,596 control chromosomes in the GnomAD database, including 36,034 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 0.28 ( 7229 hom., cov: 30)

Exomes 𝑓: 0.17 ( 28805 hom. )

Consequence

LCT
NM_002299.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0900

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:

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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=3.733337E-4).

BP6

Variant 2-135833176-C-T is Benign according to our data. Variant chr2-135833176-C-T is described in ClinVar as [Benign]. Clinvar id is 331207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135833176-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCT	NM_002299.4 linkuse as main transcript	c.655G>A	p.Val219Ile	missense_variant	2/17	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3 linkuse as main transcript	c.655G>A	p.Val219Ile	missense_variant	2/15		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7 linkuse as main transcript	c.655G>A	p.Val219Ile	missense_variant	2/17	1	NM_002299.4	ENSP00000264162	P1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41828

AN:

151670

Hom.:

7221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.454

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.479

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.265

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.319

GnomAD3 exomes

AF:

0.242

AC:

60745

AN:

251462

Hom.:

9341

AF XY:

0.241

AC XY:

32740

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.460

Gnomad AMR exome

AF:

0.241

Gnomad ASJ exome

AF:

0.489

Gnomad EAS exome

AF:

0.395

Gnomad SAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.170

AC:

248786

AN:

1460808

Hom.:

28805

Cov.:

AF XY:

0.176

AC XY:

127751

AN XY:

726774

show subpopulations

Gnomad4 AFR exome

AF:

0.465

Gnomad4 AMR exome

AF:

0.246

Gnomad4 ASJ exome

AF:

0.485

Gnomad4 EAS exome

AF:

0.332

Gnomad4 SAS exome

AF:

0.272

Gnomad4 FIN exome

AF:

0.139

Gnomad4 NFE exome

AF:

0.135

Gnomad4 OTH exome

AF:

0.220

GnomAD4 genome

AF:

0.276

AC:

41883

AN:

151788

Hom.:

7229

Cov.:

AF XY:

0.276

AC XY:

20473

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.454

Gnomad4 AMR

AF:

0.302

Gnomad4 ASJ

AF:

0.479

Gnomad4 EAS

AF:

0.379

Gnomad4 SAS

AF:

0.264

Gnomad4 FIN

AF:

0.134

Gnomad4 NFE

AF:

0.166

Gnomad4 OTH

AF:

0.323

Alfa

AF:

0.215

Hom.:

8070

Bravo

AF:

0.298

TwinsUK

AF:

0.129

AC:

479

ALSPAC

AF:

0.121

AC:

468

ESP6500AA

AF:

0.444

AC:

1957

ESP6500EA

AF:

0.181

AC:

1558

ExAC

AF:

0.244

AC:

29589

Asia WGS

AF:

0.288

AC:

1002

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 27060170) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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

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 12, 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

0.089

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.7

DANN

Benign

0.13

DEOGEN2

Benign

0.24

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.55

MetaRNN

Benign

0.00037

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.50

MutationTaster

Benign

1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

0.010

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

0.48

Polyphen

0.0090

Vest4

0.066

MPC

0.19

ClinPred

0.0057

GERP RS

2.8

Varity_R

0.042

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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