rs2304371

Positions:

• chr2-135803987-G-A
• chr2-135803987-G-C
• chr2-135803987-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002299.4(LCT):​c.4606C>T​(p.Leu1536=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,613,694 control chromosomes in the GnomAD database, including 536,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (39129 hom., cov: 32)
  • Exomes 𝑓: 0.82 (497659 hom.)
• Consequence: LCT NM_002299.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.196

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-135803987-G-A is Benign according to our data. Variant chr2-135803987-G-A is described in ClinVar as [Benign]. Clinvar id is 331172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135803987-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.196 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCT	NM_002299.4	c.4606C>T	p.Leu1536=	synonymous_variant	11/17	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3	c.4606C>T	p.Leu1536=	synonymous_variant	11/15		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.4606C>T	p.Leu1536=	synonymous_variant	11/17	1	NM_002299.4	ENSP00000264162	P1
LCT	ENST00000452974.1	c.2902C>T	p.Leu968=	synonymous_variant, NMD_transcript_variant	5/7	1		ENSP00000391231

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106404 AN: 151974 Hom.: 39124 Cov.: 32

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.658

GnomAD3 exomes AF: 0.758 AC: 190438 AN: 251288 Hom.: 74188 AF XY: 0.758 AC XY: 102927 AN XY: 135800

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.765

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.785

Gnomad SAS exome AF: 0.735

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.819 AC: 1196747 AN: 1461602 Hom.: 497659 Cov.: 52 AF XY: 0.813 AC XY: 591292 AN XY: 727112

Gnomad4 AFR exome AF: 0.458

Gnomad4 AMR exome AF: 0.760

Gnomad4 ASJ exome AF: 0.516

Gnomad4 EAS exome AF: 0.808

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.837

Gnomad4 NFE exome AF: 0.849

Gnomad4 OTH exome AF: 0.771

GnomAD4 genome AF: 0.700 AC: 106457 AN: 152092 Hom.: 39129 Cov.: 32 AF XY: 0.702 AC XY: 52150 AN XY: 74336

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.700

Gnomad4 ASJ AF: 0.518

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.746

Gnomad4 FIN AF: 0.844

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.654

Alfa AF: 0.739 Hom.: 50045

Bravo AF: 0.682

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:2

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

Congenital lactase deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

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
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.3
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs2304371; hg19: chr2-136561557;