dbSNP rs121908937: LCT:p.Gln268His (chr2-135829593-C-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_002299.4(LCT):c.804G>C(p.Gln268His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LCT
NM_002299.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.30

Publications

8 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-135829593-C-G is Pathogenic according to our data. Variant chr2-135829593-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6588.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCT	NM_002299.4 link	c.804G>C	p.Gln268His	missense_variant, splice_region_variant	Exon 3 of 17	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3 link	c.804G>C	p.Gln268His	missense_variant, splice_region_variant	Exon 3 of 15		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7 link	c.804G>C	p.Gln268His	missense_variant, splice_region_variant	Exon 3 of 17	1	NM_002299.4	ENSP00000264162.2
LCT-AS1	ENST00000769912.1 link	n.*45C>G		downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457934

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725682

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108464

Other (OTH)

AF:

0.00

AC:

AN:

60258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital lactase deficiency

Pathogenic:1

Feb 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

PhyloP100

4.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.77

REVEL

Benign

0.15

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.42

MutPred

0.73

Loss of disorder (P = 0.1236);

MVP

0.64

MPC

0.81

ClinPred

0.96

GERP RS

5.2

Varity_R

0.42

gMVP

0.61

Mutation Taster

=35/65

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

Splicevardb

3.0

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over