2-135833176-C-T

Variant names:

• chr2-135833176-C-T
• rs3754689
• NM_002299.4:c.655G>A

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.655G>A​(p.Val219Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,612,596 control chromosomes in the GnomAD database, including 36,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V219V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (7229 hom., cov: 30)
  • Exomes 𝑓: 0.17 (28805 hom.)
• Consequence: LCT NM_002299.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0900
• Publications: 63 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 (MetaRNN=3.733337E-4).
• BP6: Variant 2-135833176-C-T is Benign according to our data. Variant chr2-135833176-C-T is described in ClinVar as Benign. ClinVar VariationId is 331207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

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.655G>A	p.Val219Ile	missense	Exon 2 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.655G>A	p.Val219Ile	missense	Exon 2 of 17	ENSP00000264162.2

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41828 AN: 151670 Hom.: 7221 Cov.: 30

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.242 AC: 60745 AN: 251462 AF XY: 0.241

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.489

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.170 AC: 248786 AN: 1460808 Hom.: 28805 Cov.: 32 AF XY: 0.176 AC XY: 127751 AN XY: 726774

African (AFR) AF: 0.465 AC: 15570 AN: 33448

American (AMR) AF: 0.246 AC: 10983 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 12672 AN: 26116

East Asian (EAS) AF: 0.332 AC: 13191 AN: 39686

South Asian (SAS) AF: 0.272 AC: 23443 AN: 86238

European-Finnish (FIN) AF: 0.139 AC: 7449 AN: 53412

Middle Eastern (MID) AF: 0.383 AC: 2205 AN: 5758

European-Non Finnish (NFE) AF: 0.135 AC: 149998 AN: 1111080

Other (OTH) AF: 0.220 AC: 13275 AN: 60348

GnomAD4 genome AF: 0.276 AC: 41883 AN: 151788 Hom.: 7229 Cov.: 30 AF XY: 0.276 AC XY: 20473 AN XY: 74134

African (AFR) AF: 0.454 AC: 18760 AN: 41346

American (AMR) AF: 0.302 AC: 4600 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1661 AN: 3470

East Asian (EAS) AF: 0.379 AC: 1939 AN: 5120

South Asian (SAS) AF: 0.264 AC: 1269 AN: 4806

European-Finnish (FIN) AF: 0.134 AC: 1409 AN: 10540

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11301 AN: 67962

Other (OTH) AF: 0.323 AC: 680 AN: 2108

Alfa AF: 0.218 Hom.: 17418

Bravo AF: 0.298

TwinsUK AF: 0.129 AC: 479

ALSPAC AF: 0.121 AC: 468

ESP6500AA AF: 0.444 AC: 1957

ESP6500EA AF: 0.181 AC: 1558

ExAC AF: 0.244 AC: 29589

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital lactase deficiency (2)
-	-	2	not specified (2)
-	-	1	Lactose intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.7
DANN	Benign	0.13
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.00037	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.50	N
PhyloP100		0.090
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.033
Sift	Benign	1.0	T
Sift4G	Benign	0.48	T
Polyphen		0.0090	B
Vest4		0.066
MPC		0.19
ClinPred		0.0057	T
GERP RS		2.8
Varity_R		0.042
gMVP		0.25
Mutation Taster		=97/3	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: rs3754689; hg19: chr2-136590746; COSMIC: COSV51544338;