rs200994158

Variant names:

• chr2-135788314-T-G
• rs200994158
• NM_002299.4:c.*10A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002299.4(LCT):​c.*10A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,597,068 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (20 hom.)
• Consequence: LCT NM_002299.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.712
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.*10A>C		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.*10A>C		3_prime_UTR	Exon 17 of 17	ENSP00000264162.2	P09848

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152158 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00406 AC: 1018 AN: 250490 AF XY: 0.00411

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00301 AC: 4349 AN: 1444792 Hom.: 20 Cov.: 32 AF XY: 0.00305 AC XY: 2193 AN XY: 720036

African (AFR) AF: 0.000211 AC: 7 AN: 33100

American (AMR) AF: 0.00248 AC: 111 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26036

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39642

South Asian (SAS) AF: 0.00218 AC: 187 AN: 85926

European-Finnish (FIN) AF: 0.0183 AC: 952 AN: 52104

Middle Eastern (MID) AF: 0.00219 AC: 12 AN: 5484

European-Non Finnish (NFE) AF: 0.00261 AC: 2871 AN: 1097948

Other (OTH) AF: 0.00286 AC: 171 AN: 59848

GnomAD4 genome AF: 0.00368 AC: 561 AN: 152276 Hom.: 3 Cov.: 33 AF XY: 0.00446 AC XY: 332 AN XY: 74458

African (AFR) AF: 0.000554 AC: 23 AN: 41550

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4820

European-Finnish (FIN) AF: 0.0235 AC: 249 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.69
DANN	Benign	0.40
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism

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: rs200994158; hg19: chr2-136545884;