rs3769012

Variant names:

• chr2-135798910-G-A
• rs3769012
• NM_002299.4:c.4867-772C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002299.4(LCT):​c.4867-772C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,054 control chromosomes in the GnomAD database, including 2,863 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2863 hom., cov: 32)
• Consequence: LCT NM_002299.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.254
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCT	NM_002299.4	c.4867-772C>T		intron_variant	Intron 12 of 16	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3	c.4867-772C>T		intron_variant	Intron 12 of 14		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.4867-772C>T		intron_variant	Intron 12 of 16	1	NM_002299.4	ENSP00000264162.2
LCT	ENST00000452974.1	n.2960-772C>T		intron_variant	Intron 5 of 6	1		ENSP00000391231.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28003 AN: 151936 Hom.: 2863 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.251

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.184 AC: 28017 AN: 152054 Hom.: 2863 Cov.: 32 AF XY: 0.186 AC XY: 13808 AN XY: 74298

African (AFR) AF: 0.193 AC: 8009 AN: 41462

American (AMR) AF: 0.236 AC: 3613 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1408 AN: 3466

East Asian (EAS) AF: 0.161 AC: 831 AN: 5160

South Asian (SAS) AF: 0.239 AC: 1149 AN: 4808

European-Finnish (FIN) AF: 0.125 AC: 1318 AN: 10582

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.160 AC: 10897 AN: 67984

Other (OTH) AF: 0.254 AC: 536 AN: 2112

Alfa AF: 0.186 Hom.: 513

Bravo AF: 0.190

Asia WGS AF: 0.187 AC: 652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.59
DANN	Benign	0.44
PhyloP100		-0.25
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: rs3769012; hg19: chr2-136556480;