2-135788314-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4	c.*10A>C		3_prime_UTR_variant	17/17	ENST00000264162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7	c.*10A>C		3_prime_UTR_variant	17/17	1	NM_002299.4	P1

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

GnomAD3 exomes AF: 0.00406 AC: 1018 AN: 250490 Hom.: 5 AF XY: 0.00411 AC XY: 557 AN XY: 135494

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 SAS exome AF: 0.00176

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

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00286

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

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00255 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lactose intolerance Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital lactase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.69
Dann	Benign	0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs200994158; hg19: chr2-136545884;