rs1042712

Variant names:

• chr2-135788274-C-G
• rs1042712
• NM_002299.4:c.*50G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002299.4(LCT):​c.*50G>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 0.833 in 1,361,456 control chromosomes in the GnomAD database, including 477,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47297 hom., cov: 32)
  • Exomes 𝑓: 0.84 (430522 hom.)
• Consequence: LCT NM_002299.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.108
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• congenital lactase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-135788274-C-G is Benign according to our data. Variant chr2-135788274-C-G is described in ClinVar as Benign. ClinVar VariationId is 331159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCT	NM_002299.4	c.*50G>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000264162.7	NP_002290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.*50G>C		3_prime_UTR_variant	Exon 17 of 17	1	NM_002299.4	ENSP00000264162.2

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119278 AN: 152034 Hom.: 47267 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.729

GnomAD2 exomes AF: 0.796 AC: 195021 AN: 244904 AF XY: 0.792

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.808

Gnomad ASJ exome AF: 0.543

Gnomad EAS exome AF: 0.808

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.765

GnomAD4 exome AF: 0.839 AC: 1015133 AN: 1209306 Hom.: 430522 Cov.: 17 AF XY: 0.833 AC XY: 511533 AN XY: 613866

African (AFR) AF: 0.693 AC: 19865 AN: 28646

American (AMR) AF: 0.802 AC: 35626 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 13517 AN: 24628

East Asian (EAS) AF: 0.822 AC: 31736 AN: 38610

South Asian (SAS) AF: 0.746 AC: 60694 AN: 81344

European-Finnish (FIN) AF: 0.862 AC: 39038 AN: 45262

Middle Eastern (MID) AF: 0.606 AC: 2599 AN: 4292

European-Non Finnish (NFE) AF: 0.865 AC: 770248 AN: 889956

Other (OTH) AF: 0.802 AC: 41810 AN: 52164

GnomAD4 genome AF: 0.785 AC: 119363 AN: 152150 Hom.: 47297 Cov.: 32 AF XY: 0.782 AC XY: 58170 AN XY: 74372

African (AFR) AF: 0.711 AC: 29483 AN: 41474

American (AMR) AF: 0.748 AC: 11427 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1899 AN: 3472

East Asian (EAS) AF: 0.802 AC: 4150 AN: 5174

South Asian (SAS) AF: 0.748 AC: 3602 AN: 4818

European-Finnish (FIN) AF: 0.869 AC: 9214 AN: 10598

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.840 AC: 57113 AN: 68024

Other (OTH) AF: 0.726 AC: 1528 AN: 2106

Alfa AF: 0.768 Hom.: 8447

Bravo AF: 0.774

Asia WGS AF: 0.777 AC: 2701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lactose intolerance Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital lactase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.72
DANN	Benign	0.32
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042712; hg19: chr2-136545844;