rs2077508741

Variant names:

• chr2-135788382-G-C
• rs2077508741
• NM_002299.4:c.5726C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002299.4(LCT):​c.5726C>G​(p.Ser1909Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1909S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LCT NM_002299.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86
• Publications: 0 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: PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.5726C>G	p.Ser1909Cys	missense	Exon 17 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.5726C>G	p.Ser1909Cys	missense	Exon 17 of 17	ENSP00000264162.2	P09848

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461852 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.31		Loss of disorder (P = 0.0088)
MVP		0.68
MPC		1.5
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.36
Mutation Taster		=64/36	polymorphism

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: rs2077508741; hg19: chr2-136545952;