2-135788340-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 14/20 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:4
• Conservation: PhyloP100: -0.695

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LCT
• 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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCT	NM_002299.4	c.5768C>A	p.Pro1923Gln	missense_variant	17/17	ENST00000264162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCT	ENST00000264162.7	c.5768C>A	p.Pro1923Gln	missense_variant	17/17	1	NM_002299.4	P1

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

GnomAD3 exomes AF: 0.00389 AC: 978 AN: 251284 Hom.: 23 AF XY: 0.00273 AC XY: 371 AN XY: 135836

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0536

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.00316

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

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.000761 Hom.: 3

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Lactose intolerance Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

LCT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital lactase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs114828879; hg19: chr2-136545910; COSMIC: COSV99078432; COSMIC: COSV99078432;