chr2-135836588-G-A

Variant names:

• chr2-135836588-G-A
• rs2236783
• NM_002299.4:c.582C>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.582C>T​(p.Thr194Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,613,296 control chromosomes in the GnomAD database, including 393,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (23867 hom., cov: 31)
  • Exomes 𝑓: 0.69 (370010 hom.)
• Consequence: LCT NM_002299.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0840
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-135836588-G-A is Benign according to our data. Variant chr2-135836588-G-A is described in ClinVar as Benign. ClinVar VariationId is 331210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.084 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 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.582C>T	p.Thr194Thr	synonymous	Exon 1 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.582C>T	p.Thr194Thr	synonymous	Exon 1 of 17	ENSP00000264162.2

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77346 AN: 151828 Hom.: 23865 Cov.: 31

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.448

GnomAD2 exomes AF: 0.549 AC: 138019 AN: 251478 AF XY: 0.552

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.369

Gnomad FIN exome AF: 0.709

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.688 AC: 1006069 AN: 1461352 Hom.: 370010 Cov.: 44 AF XY: 0.677 AC XY: 492412 AN XY: 727010

African (AFR) AF: 0.196 AC: 6548 AN: 33470

American (AMR) AF: 0.400 AC: 17906 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7944 AN: 26136

East Asian (EAS) AF: 0.383 AC: 15195 AN: 39698

South Asian (SAS) AF: 0.419 AC: 36143 AN: 86236

European-Finnish (FIN) AF: 0.707 AC: 37755 AN: 53418

Middle Eastern (MID) AF: 0.246 AC: 1417 AN: 5766

European-Non Finnish (NFE) AF: 0.761 AC: 846069 AN: 1111528

Other (OTH) AF: 0.614 AC: 37092 AN: 60376

GnomAD4 genome AF: 0.509 AC: 77360 AN: 151944 Hom.: 23867 Cov.: 31 AF XY: 0.500 AC XY: 37147 AN XY: 74248

African (AFR) AF: 0.222 AC: 9195 AN: 41428

American (AMR) AF: 0.388 AC: 5919 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1068 AN: 3470

East Asian (EAS) AF: 0.356 AC: 1828 AN: 5142

South Asian (SAS) AF: 0.381 AC: 1836 AN: 4814

European-Finnish (FIN) AF: 0.711 AC: 7508 AN: 10554

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48298 AN: 67958

Other (OTH) AF: 0.443 AC: 934 AN: 2106

Alfa AF: 0.566 Hom.: 26897

Bravo AF: 0.475

Asia WGS AF: 0.381 AC: 1327 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.55
PhyloP100		-0.084
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: rs2236783; hg19: chr2-136594158; COSMIC: COSV51464813; COSMIC: COSV51464813;