Genetic Variant LCT:c.4976+74A>C (chr2-135797955-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002299.4(LCT):c.4976+74A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 842,670 control chromosomes in the GnomAD database, including 16,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2891 hom., cov: 32)

Exomes 𝑓: 0.18 ( 14004 hom. )

Consequence

LCT
NM_002299.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.65

Publications

11 publications found

Variant links:

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

LCT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 2-135797955-T-G is Benign according to our data. Variant chr2-135797955-T-G is described in ClinVar as Benign. ClinVar VariationId is 1227196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCT	NM_002299.4 link	c.4976+74A>C		intron_variant	Intron 13 of 16	ENST00000264162.7	NP_002290.2
LCT	XM_017004088.3 link	c.4976+74A>C		intron_variant	Intron 13 of 14		XP_016859577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCT	ENST00000264162.7 link	c.4976+74A>C		intron_variant	Intron 13 of 16	1	NM_002299.4	ENSP00000264162.2
LCT	ENST00000452974.1 link	n.*57+74A>C		intron_variant	Intron 6 of 6	1		ENSP00000391231.1

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28176

AN:

152058

Hom.:

2894

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.235

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.163

Gnomad OTH

AF:

0.249

GnomAD4 exome

AF:

0.183

AC:

126401

AN:

690494

Hom.:

14004

AF XY:

0.189

AC XY:

70317

AN XY:

372356

show subpopulations

African (AFR)

AF:

0.195

AC:

3714

AN:

19094

American (AMR)

AF:

0.189

AC:

8227

AN:

43516

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

9272

AN:

21480

East Asian (EAS)

AF:

0.122

AC:

4449

AN:

36344

South Asian (SAS)

AF:

0.232

AC:

16557

AN:

71246

European-Finnish (FIN)

AF:

0.142

AC:

6549

AN:

46186

Middle Eastern (MID)

AF:

0.358

AC:

1470

AN:

4104

European-Non Finnish (NFE)

AF:

0.167

AC:

68985

AN:

413248

Other (OTH)

AF:

0.203

AC:

7178

AN:

35276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

6273

12546

18818

25091

31364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

906

1812

2718

3624

4530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.185

AC:

28190

AN:

152176

Hom.:

2891

Cov.:

AF XY:

0.187

AC XY:

13891

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.194

AC:

8042

AN:

41522

American (AMR)

AF:

0.235

AC:

3594

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1499

AN:

3468

East Asian (EAS)

AF:

0.135

AC:

696

AN:

5170

South Asian (SAS)

AF:

0.224

AC:

1083

AN:

4828

European-Finnish (FIN)

AF:

0.134

AC:

1423

AN:

10590

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.163

AC:

11058

AN:

68000

Other (OTH)

AF:

0.252

AC:

533

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1173

2346

3520

4693

5866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.136

Hom.:

410

Bravo

AF:

0.191

Asia WGS

AF:

0.169

AC:

587

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.080

(source)

DANN

Benign

0.25

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over