chr2-135788340-G-T

Variant names:

• chr2-135788340-G-T
• rs114828879
• NM_002299.4:c.5768C>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.5768C>A​(p.Pro1923Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,612,928 control chromosomes in the GnomAD database, including 105 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1923L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (55 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (50 hom.)
• Consequence: LCT NM_002299.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.695
• Publications: 7 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=0.0015354455).
• BP6: Variant 2-135788340-G-T is Benign according to our data. Variant chr2-135788340-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 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.5768C>A	p.Pro1923Gln	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.5768C>A	p.Pro1923Gln	missense	Exon 17 of 17	ENSP00000264162.2	P09848

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2410 AN: 152128 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00389 AC: 978 AN: 251284 AF XY: 0.00273

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00149 AC: 2172 AN: 1460682 Hom.: 50 Cov.: 34 AF XY: 0.00131 AC XY: 949 AN XY: 726718

African (AFR) AF: 0.0536 AC: 1792 AN: 33442

American (AMR) AF: 0.00293 AC: 131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5686

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111252

Other (OTH) AF: 0.00316 AC: 191 AN: 60354

GnomAD4 genome AF: 0.0158 AC: 2412 AN: 152246 Hom.: 55 Cov.: 33 AF XY: 0.0147 AC XY: 1095 AN XY: 74444

African (AFR) AF: 0.0549 AC: 2277 AN: 41510

American (AMR) AF: 0.00602 AC: 92 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00487 Hom.: 31

Bravo AF: 0.0182

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00475 AC: 577

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital lactase deficiency (1)
-	-	1	Lactose intolerance (1)
-	-	1	LCT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.053
DANN	Benign	0.58
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.69
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.0070
Sift	Benign	0.24	T
Sift4G	Benign	0.20	T
Polyphen		0.0050	B
Vest4		0.079
MVP		0.092
MPC		0.58
ClinPred		0.0058	T
GERP RS		-4.3
Varity_R		0.031
gMVP		0.31
Mutation Taster		=96/4	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: rs114828879; hg19: chr2-136545910; COSMIC: COSV99078432; COSMIC: COSV99078432;