rs3739022

Variant names:

• chr2-135804902-G-A
• rs3739022
• NM_002299.4:c.4329C>T
• LCT p.Gly1443Gly

Your query was ambiguous. Multiple possible variants found:

• chr2-135804902-G-A
• chr2-135804902-G-C
• chr2-135804902-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.4329C>T​(p.Gly1443Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,826 control chromosomes in the GnomAD database, including 16,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2414 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13993 hom.)
• Consequence: LCT NM_002299.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.48
• Publications: 20 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-135804902-G-A is Benign according to our data. Variant chr2-135804902-G-A is described in ClinVar as Benign. ClinVar VariationId is 331176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.319 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.4329C>T	p.Gly1443Gly	synonymous	Exon 10 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.4329C>T	p.Gly1443Gly	synonymous	Exon 10 of 17	ENSP00000264162.2	P09848
	LCT	ENST00000452974.1	TSL:1	n.2625C>T		non_coding_transcript_exon	Exon 4 of 7	ENSP00000391231.1	H0Y4E4

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24529 AN: 151962 Hom.: 2414 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.0985

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.169 AC: 42525 AN: 251266 AF XY: 0.171

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.199

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.117 AC: 170360 AN: 1461746 Hom.: 13993 Cov.: 34 AF XY: 0.122 AC XY: 88927 AN XY: 727164

African (AFR) AF: 0.222 AC: 7429 AN: 33476

American (AMR) AF: 0.263 AC: 11743 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4671 AN: 26134

East Asian (EAS) AF: 0.218 AC: 8663 AN: 39696

South Asian (SAS) AF: 0.295 AC: 25475 AN: 86252

European-Finnish (FIN) AF: 0.128 AC: 6830 AN: 53414

Middle Eastern (MID) AF: 0.329 AC: 1899 AN: 5766

European-Non Finnish (NFE) AF: 0.0858 AC: 95388 AN: 1111912

Other (OTH) AF: 0.137 AC: 8262 AN: 60394

GnomAD4 genome AF: 0.161 AC: 24560 AN: 152080 Hom.: 2414 Cov.: 32 AF XY: 0.170 AC XY: 12615 AN XY: 74336

African (AFR) AF: 0.213 AC: 8851 AN: 41482

American (AMR) AF: 0.250 AC: 3812 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3466

East Asian (EAS) AF: 0.206 AC: 1063 AN: 5160

South Asian (SAS) AF: 0.332 AC: 1599 AN: 4810

European-Finnish (FIN) AF: 0.130 AC: 1376 AN: 10594

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.0985 AC: 6695 AN: 67996

Other (OTH) AF: 0.185 AC: 389 AN: 2104

Alfa AF: 0.129 Hom.: 4970

Bravo AF: 0.168

Asia WGS AF: 0.295 AC: 1026 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.052
DANN	Benign	0.51
PhyloP100		-3.5
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3739022;

hg19: chr2-136562472;

COSMIC: COSV51548741;