rs2304371

Variant names:

• chr2-135803987-G-A
• rs2304371
• NM_002299.4:c.4606C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002299.4(LCT):​c.4606C>T​(p.Leu1536Leu) 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
• Publications: 40 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 331172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002299.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCT	NM_002299.4	MANE Select	c.4606C>T	p.Leu1536Leu	synonymous	Exon 11 of 17	NP_002290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCT	ENST00000264162.7	TSL:1 MANE Select	c.4606C>T	p.Leu1536Leu	synonymous	Exon 11 of 17	ENSP00000264162.2	P09848
	LCT	ENST00000452974.1	TSL:1	n.2902C>T		non_coding_transcript_exon	Exon 5 of 7	ENSP00000391231.1	H0Y4E4

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

GnomAD2 exomes AF: 0.758 AC: 190438 AN: 251288 AF XY: 0.758

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 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

African (AFR) AF: 0.458 AC: 15316 AN: 33468

American (AMR) AF: 0.760 AC: 33991 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 13492 AN: 26132

East Asian (EAS) AF: 0.808 AC: 32060 AN: 39700

South Asian (SAS) AF: 0.738 AC: 63601 AN: 86236

European-Finnish (FIN) AF: 0.837 AC: 44703 AN: 53410

Middle Eastern (MID) AF: 0.588 AC: 3387 AN: 5758

European-Non Finnish (NFE) AF: 0.849 AC: 943665 AN: 1111798

Other (OTH) AF: 0.771 AC: 46532 AN: 60386

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

African (AFR) AF: 0.478 AC: 19818 AN: 41448

American (AMR) AF: 0.700 AC: 10713 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1796 AN: 3468

East Asian (EAS) AF: 0.780 AC: 4019 AN: 5154

South Asian (SAS) AF: 0.746 AC: 3599 AN: 4826

European-Finnish (FIN) AF: 0.844 AC: 8929 AN: 10584

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.813 AC: 55271 AN: 68002

Other (OTH) AF: 0.654 AC: 1383 AN: 2114

Alfa AF: 0.752 Hom.: 120272

Bravo AF: 0.682

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital lactase deficiency (2)
-	-	2	not specified (2)
-	-	1	Lactose intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.3
DANN	Benign	0.68
PhyloP100		0.20
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304371; hg19: chr2-136561557; COSMIC: COSV107253943;