chr2-135814412-T-A

Variant names:

• chr2-135814412-T-A
• rs4954445
• NM_002299.4:c.1708-1456A>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.1708-1456A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,084 control chromosomes in the GnomAD database, including 2,422 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 0.16 (2422 hom., cov: 32)
• Consequence: LCT NM_002299.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCT	NM_002299.4	c.1708-1456A>T		intron_variant	Intron 6 of 16	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3	c.1708-1456A>T		intron_variant	Intron 6 of 14		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.1708-1456A>T		intron_variant	Intron 6 of 16	1	NM_002299.4	ENSP00000264162.2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24568 AN: 151966 Hom.: 2421 Cov.: 32

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.0983

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.162 AC: 24600 AN: 152084 Hom.: 2422 Cov.: 32 AF XY: 0.170 AC XY: 12621 AN XY: 74328

African (AFR) AF: 0.215 AC: 8911 AN: 41470

American (AMR) AF: 0.250 AC: 3809 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3472

East Asian (EAS) AF: 0.208 AC: 1076 AN: 5184

South Asian (SAS) AF: 0.327 AC: 1578 AN: 4826

European-Finnish (FIN) AF: 0.130 AC: 1374 AN: 10562

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

European-Non Finnish (NFE) AF: 0.0983 AC: 6686 AN: 67994

Other (OTH) AF: 0.185 AC: 391 AN: 2112

Alfa AF: 0.137 Hom.: 207

Bravo AF: 0.169

Asia WGS AF: 0.293 AC: 1018 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.52
PhyloP100		-0.12
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: rs4954445; hg19: chr2-136571982;