chr2-135804165-G-A

Variant names:

• chr2-135804165-G-A
• rs2304370
• NM_002299.4:c.4465-37C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -1.33
• Publications: 18 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: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LCT	NM_002299.4	c.4465-37C>T		intron_variant	Intron 10 of 16	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3	c.4465-37C>T		intron_variant	Intron 10 of 14		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7	c.4465-37C>T		intron_variant	Intron 10 of 16	1	NM_002299.4	ENSP00000264162.2
LCT	ENST00000452974.1	n.2761-37C>T		intron_variant	Intron 4 of 6	1		ENSP00000391231.1

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

GnomAD2 exomes AF: 0.226 AC: 56199 AN: 248480 AF XY: 0.230

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 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

African (AFR) AF: 0.323 AC: 10385 AN: 32148

American (AMR) AF: 0.229 AC: 10206 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 11924 AN: 25790

East Asian (EAS) AF: 0.193 AC: 7585 AN: 39400

South Asian (SAS) AF: 0.262 AC: 22246 AN: 84812

European-Finnish (FIN) AF: 0.164 AC: 8445 AN: 51448

Middle Eastern (MID) AF: 0.435 AC: 1954 AN: 4490

European-Non Finnish (NFE) AF: 0.153 AC: 161170 AN: 1051848

Other (OTH) AF: 0.216 AC: 12568 AN: 58116

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

African (AFR) AF: 0.312 AC: 12929 AN: 41474

American (AMR) AF: 0.271 AC: 4136 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1624 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1143 AN: 5174

South Asian (SAS) AF: 0.252 AC: 1215 AN: 4812

European-Finnish (FIN) AF: 0.157 AC: 1662 AN: 10594

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12660 AN: 67982

Other (OTH) AF: 0.301 AC: 636 AN: 2110

Alfa AF: 0.228 Hom.: 3668

Bravo AF: 0.247

Asia WGS AF: 0.221 AC: 768 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital lactase deficiency Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.69
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304370; hg19: chr2-136561735; COSMIC: COSV51548318;