rs3739022

chr2-135804902-G-A

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.4329C>T(p.Gly1443=) 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

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=-0.76).
• BP6: Variant 2-135804902-G-A is Benign according to our data. Variant chr2-135804902-G-A is described in ClinVar as [Benign]. Clinvar id is 331176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-135804902-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4	c.4329C>T	p.Gly1443=	synonymous_variant	10/17	ENST00000264162.7
LCT	XM_017004088.3	c.4329C>T	p.Gly1443=	synonymous_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7	c.4329C>T	p.Gly1443=	synonymous_variant	10/17	1	NM_002299.4	P1
LCT	ENST00000452974.1	c.2625C>T	p.Gly875=	synonymous_variant, NMD_transcript_variant	4/7	1

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

GnomAD3 exomes AF: 0.169 AC: 42525 AN: 251266 Hom.: 4628 AF XY: 0.171 AC XY: 23225 AN XY: 135816

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 SAS exome AF: 0.299

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

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.295

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.0858

Gnomad4 OTH exome AF: 0.137

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

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.0985

Gnomad4 OTH AF: 0.185

Alfa AF: 0.124 Hom.: 2900

Bravo AF: 0.168

Asia WGS AF: 0.295 AC: 1026 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Lactose intolerance Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital lactase deficiency 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	-0.76
Cadd	Benign	0.052
Dann	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs3739022; hg19: chr2-136562472; COSMIC: COSV51548741;