2-135787999-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002299.4(LCT):c.*325G>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 0.0157 in 364,086 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 32)
  • Exomes 𝑓: 0.017 (51 hom.)
• Consequence: LCT NM_002299.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.407

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-135787999-C-G is Benign according to our data. Variant chr2-135787999-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331156.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0135 (2050/152234) while in subpopulation SAS AF= 0.0312 (150/4814). AF 95% confidence interval is 0.0271. There are 28 homozygotes in gnomad4. There are 1095 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4	c.*325G>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.*325G>C		3_prime_UTR_variant	17/17	1	NM_002299.4	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2053 AN: 152116 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0172 AC: 3652 AN: 211852 Hom.: 51 Cov.: 0 AF XY: 0.0188 AC XY: 2136 AN XY: 113364

Gnomad4 AFR exome AF: 0.00318

Gnomad4 AMR exome AF: 0.0344

Gnomad4 ASJ exome AF: 0.0389

Gnomad4 EAS exome AF: 0.00306

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0135 AC: 2050 AN: 152234 Hom.: 28 Cov.: 32 AF XY: 0.0147 AC XY: 1095 AN XY: 74418

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0312

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00677 Hom.: 2

Bravo AF: 0.0134

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.4
Dann	Benign	0.57

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: rs62170085; hg19: chr2-136545569;