rs2322659

Variant names:

• chr2-135798089-T-C
• rs2322659
• NM_002299.4:c.4916A>G

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.4916A>G​(p.Asn1639Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,611,080 control chromosomes in the GnomAD database, including 423,167 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28339 hom., cov: 30)
  • Exomes 𝑓: 0.72 (394828 hom.)
• Consequence: LCT NM_002299.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.919
• Publications: 80 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1393369E-6).
• BP6: Variant 2-135798089-T-C is Benign according to our data. Variant chr2-135798089-T-C is described in ClinVar as Benign. ClinVar VariationId is 331168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.732 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.4916A>G	p.Asn1639Ser	missense	Exon 13 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.4916A>G	p.Asn1639Ser	missense	Exon 13 of 17	ENSP00000264162.2	P09848
	LCT	ENST00000452974.1	TSL:1	n.3009A>G		non_coding_transcript_exon	Exon 6 of 7	ENSP00000391231.1	H0Y4E4

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88941 AN: 151840 Hom.: 28336 Cov.: 30

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.515

GnomAD2 exomes AF: 0.605 AC: 152212 AN: 251436 AF XY: 0.604

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.726

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.720 AC: 1050134 AN: 1459122 Hom.: 394828 Cov.: 39 AF XY: 0.709 AC XY: 515018 AN XY: 726126

African (AFR) AF: 0.369 AC: 12324 AN: 33410

American (AMR) AF: 0.497 AC: 22226 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9692 AN: 26122

East Asian (EAS) AF: 0.498 AC: 19747 AN: 39688

South Asian (SAS) AF: 0.464 AC: 40024 AN: 86212

European-Finnish (FIN) AF: 0.732 AC: 39073 AN: 53374

Middle Eastern (MID) AF: 0.305 AC: 1760 AN: 5762

European-Non Finnish (NFE) AF: 0.780 AC: 865737 AN: 1109532

Other (OTH) AF: 0.656 AC: 39551 AN: 60300

GnomAD4 genome AF: 0.586 AC: 88972 AN: 151958 Hom.: 28339 Cov.: 30 AF XY: 0.576 AC XY: 42816 AN XY: 74272

African (AFR) AF: 0.396 AC: 16404 AN: 41432

American (AMR) AF: 0.460 AC: 7019 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1286 AN: 3468

East Asian (EAS) AF: 0.472 AC: 2417 AN: 5122

South Asian (SAS) AF: 0.438 AC: 2108 AN: 4812

European-Finnish (FIN) AF: 0.735 AC: 7783 AN: 10592

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.737 AC: 50084 AN: 67950

Other (OTH) AF: 0.510 AC: 1076 AN: 2108

Alfa AF: 0.664 Hom.: 129788

Bravo AF: 0.561

TwinsUK AF: 0.784 AC: 2907

ALSPAC AF: 0.799 AC: 3081

ESP6500AA AF: 0.407 AC: 1794

ESP6500EA AF: 0.726 AC: 6240

ExAC AF: 0.606 AC: 73536

Asia WGS AF: 0.454 AC: 1580 AN: 3478

ClinVar

ClinVar submissions

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	0.059
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.32
DANN	Benign	0.74
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.53	N
PhyloP100		-0.92
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.12
Sift	Benign	0.13	T
Sift4G	Benign	0.49	T
Polyphen		0.013	B
Vest4		0.056
MPC		0.52
ClinPred		0.011	T
GERP RS		-8.9
Varity_R		0.044
gMVP		0.64
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2322659; hg19: chr2-136555659; COSMIC: COSV51548333;