Variant 2-135787999-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002299.4(LCT):c.*325G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 364,086 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 28 hom., cov: 32)

Exomes 𝑓: 0.017 ( 51 hom. )

Consequence

LCT
NM_002299.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.407

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-135787999-C-G is Benign according to our data. Variant chr2-135787999-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331156.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0135 (2050/152234) while in subpopulation SAS AF= 0.0312 (150/4814). AF 95% confidence interval is 0.0271. There are 28 homozygotes in gnomad4. There are 1095 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4 linkuse as main transcript	c.*325G>C		3_prime_UTR_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.*325G>C		3_prime_UTR_variant	17/17	1	NM_002299.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2053

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0283

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0136

Gnomad OTH

AF:

0.0144

GnomAD4 exome

AF:

0.0172

AC:

3652

AN:

211852

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

2136

AN XY:

113364

show subpopulations

Gnomad4 AFR exome

AF:

0.00318

Gnomad4 AMR exome

AF:

0.0344

Gnomad4 ASJ exome

AF:

0.0389

Gnomad4 EAS exome

AF:

0.00306

Gnomad4 SAS exome

AF:

0.0305

Gnomad4 FIN exome

AF:

0.0197

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.0177

GnomAD4 genome

AF:

0.0135

AC:

2050

AN:

152234

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1095

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00327

Gnomad4 AMR

AF:

0.0282

Gnomad4 ASJ

AF:

0.0392

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.0312

Gnomad4 FIN

AF:

0.0213

Gnomad4 NFE

AF:

0.0136

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.0134

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lactose intolerance

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital lactase deficiency

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.4

DANN

Benign

0.57

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