chr2-135787999-C-G

Variant names:

• chr2-135787999-C-G
• rs62170085
• NM_002299.4:c.*325G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002299.4(LCT):​c.*325G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 364,086 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 32)
  • Exomes 𝑓: 0.017 (51 hom.)
• Consequence: LCT NM_002299.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.407
• Publications: 2 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-135787999-C-G is Benign according to our data. Variant chr2-135787999-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 331156.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0135 (2050/152234) while in subpopulation SAS AF = 0.0312 (150/4814). AF 95% confidence interval is 0.0271. There are 28 homozygotes in GnomAd4. There are 1095 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

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.*325G>C		3_prime_UTR	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.*325G>C		3_prime_UTR	Exon 17 of 17	ENSP00000264162.2	P09848

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2053 AN: 152116 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0172 AC: 3652 AN: 211852 Hom.: 51 Cov.: 0 AF XY: 0.0188 AC XY: 2136 AN XY: 113364

African (AFR) AF: 0.00318 AC: 21 AN: 6614

American (AMR) AF: 0.0344 AC: 291 AN: 8450

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 231 AN: 5944

East Asian (EAS) AF: 0.00306 AC: 33 AN: 10778

South Asian (SAS) AF: 0.0305 AC: 1024 AN: 33600

European-Finnish (FIN) AF: 0.0197 AC: 192 AN: 9750

Middle Eastern (MID) AF: 0.0339 AC: 30 AN: 884

European-Non Finnish (NFE) AF: 0.0131 AC: 1629 AN: 124500

Other (OTH) AF: 0.0177 AC: 201 AN: 11332

GnomAD4 genome AF: 0.0135 AC: 2050 AN: 152234 Hom.: 28 Cov.: 32 AF XY: 0.0147 AC XY: 1095 AN XY: 74418

African (AFR) AF: 0.00327 AC: 136 AN: 41540

American (AMR) AF: 0.0282 AC: 431 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5178

South Asian (SAS) AF: 0.0312 AC: 150 AN: 4814

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 925 AN: 68008

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00677 Hom.: 2

Bravo AF: 0.0134

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital lactase deficiency (1)
-	1	-	Lactose intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.57
PhyloP100		0.41
Mutation Taster		=100/0	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: rs62170085; hg19: chr2-136545569;