rs2304370

chr2-135804165-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002299.4(LCT):c.4465-37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,544,742 control chromosomes in the GnomAD database, including 31,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4869 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27096 hom.)
• Consequence: LCT NM_002299.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-135804165-G-A is Benign according to our data. Variant chr2-135804165-G-A is described in ClinVar as [Benign]. Clinvar id is 1175392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4	c.4465-37C>T		intron_variant		ENST00000264162.7
LCT	XM_017004088.3	c.4465-37C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7	c.4465-37C>T		intron_variant		1	NM_002299.4	P1
LCT	ENST00000452974.1	c.2761-37C>T		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36253 AN: 151974 Hom.: 4868 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.226 AC: 56199 AN: 248480 Hom.: 7589 AF XY: 0.230 AC XY: 30867 AN XY: 134364

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.225

Gnomad ASJ exome AF: 0.465

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.265

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.177 AC: 246483 AN: 1392650 Hom.: 27096 Cov.: 23 AF XY: 0.183 AC XY: 127667 AN XY: 696874

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.262

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.239 AC: 36278 AN: 152092 Hom.: 4869 Cov.: 32 AF XY: 0.239 AC XY: 17779 AN XY: 74342

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.301

Alfa AF: 0.227 Hom.: 2716

Bravo AF: 0.247

Asia WGS AF: 0.221 AC: 768 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Congenital lactase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.7
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2304370; hg19: chr2-136561735; COSMIC: COSV51548318;