chr2-135787878-AAC-A

Variant names:

• chr2-135787878-AAC-A
• rs140433552
• NM_002299.4:c.*444_*445delGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002299.4(LCT):​c.*444_*445delGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 180,422 control chromosomes in the GnomAD database, including 3,397 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2915 hom., cov: 28)
  • Exomes 𝑓: 0.16 (482 hom.)
• Consequence: LCT NM_002299.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.04
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-135787878-AAC-A is Benign according to our data. Variant chr2-135787878-AAC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 331154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.231 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.*444_*445delGT		3_prime_UTR	Exon 17 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.*444_*445delGT		3_prime_UTR	Exon 17 of 17	ENSP00000264162.2	P09848

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28325 AN: 152032 Hom.: 2917 Cov.: 28

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.163 AC: 4619 AN: 28272 Hom.: 482 AF XY: 0.169 AC XY: 2562 AN XY: 15120

African (AFR) AF: 0.189 AC: 117 AN: 620

American (AMR) AF: 0.205 AC: 665 AN: 3242

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 186 AN: 504

East Asian (EAS) AF: 0.174 AC: 341 AN: 1962

South Asian (SAS) AF: 0.205 AC: 828 AN: 4036

European-Finnish (FIN) AF: 0.110 AC: 83 AN: 752

Middle Eastern (MID) AF: 0.364 AC: 24 AN: 66

European-Non Finnish (NFE) AF: 0.138 AC: 2180 AN: 15832

Other (OTH) AF: 0.155 AC: 195 AN: 1258

GnomAD4 genome AF: 0.186 AC: 28338 AN: 152150 Hom.: 2915 Cov.: 28 AF XY: 0.188 AC XY: 13994 AN XY: 74390

African (AFR) AF: 0.196 AC: 8155 AN: 41510

American (AMR) AF: 0.238 AC: 3630 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1525 AN: 3468

East Asian (EAS) AF: 0.179 AC: 928 AN: 5174

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4820

European-Finnish (FIN) AF: 0.131 AC: 1385 AN: 10600

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10870 AN: 68000

Other (OTH) AF: 0.253 AC: 534 AN: 2110

Alfa AF: 0.180 Hom.: 339

Bravo AF: 0.193

Asia WGS AF: 0.185 AC: 643 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital lactase deficiency (1)
-	-	1	Lactose intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
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: rs140433552; hg19: chr2-136545448; COSMIC: COSV51543502; COSMIC: COSV51543502;