2-135798612-T-C

Variant names:

• chr2-135798612-T-C
• rs3769013
• NM_002299.4:c.4867-474A>G

Variant summary

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

The NM_002299.4(LCT):​c.4867-474A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.792 in 152,224 control chromosomes in the GnomAD database, including 48,171 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 0.79 (48171 hom., cov: 33)
• Consequence: LCT NM_002299.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.466
• 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: PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.83 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.4867-474A>G		intron	N/A	NP_002290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCT	ENST00000264162.7	TSL:1 MANE Select	c.4867-474A>G		intron	N/A	ENSP00000264162.2	P09848
	LCT	ENST00000452974.1	TSL:1	n.2960-474A>G		intron	N/A	ENSP00000391231.1	H0Y4E4

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120497 AN: 152106 Hom.: 48133 Cov.: 33

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.835

Gnomad OTH AF: 0.732

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

GnomAD4 genome AF: 0.792 AC: 120586 AN: 152224 Hom.: 48171 Cov.: 33 AF XY: 0.791 AC XY: 58864 AN XY: 74438

African (AFR) AF: 0.738 AC: 30657 AN: 41524

American (AMR) AF: 0.755 AC: 11544 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1920 AN: 3470

East Asian (EAS) AF: 0.827 AC: 4281 AN: 5178

South Asian (SAS) AF: 0.764 AC: 3692 AN: 4830

European-Finnish (FIN) AF: 0.866 AC: 9187 AN: 10610

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.835 AC: 56818 AN: 68006

Other (OTH) AF: 0.729 AC: 1541 AN: 2114

Alfa AF: 0.796 Hom.: 119956

Bravo AF: 0.783

Asia WGS AF: 0.805 AC: 2799 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.6
DANN	Benign	0.63
PhyloP100		-0.47
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: rs3769013; hg19: chr2-136556182;