rs2516739

Variant names:

• chr16-2047157-G-A
• rs2516739
• NM_002528.7:c.115+552C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2047157-G-A
• chr16-2047157-G-C
• chr16-2047157-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002528.7(NTHL1):​c.115+552C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 155,340 control chromosomes in the GnomAD database, including 8,243 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (8187 hom., cov: 33)
  • Exomes 𝑓: 0.17 (56 hom.)
• Consequence: NTHL1 NM_002528.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.711
• Publications: 34 publications found

Genes affected

NTHL1 (HGNC:8028): (nth like DNA glycosylase 1) The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002528.7. 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
	NTHL1	NM_002528.7	MANE Select	c.115+552C>T		intron	N/A	NP_002519.2	P78549-2
	NTHL1	NM_001318193.2		c.115+552C>T		intron	N/A	NP_001305122.2
	NTHL1	NM_001318194.2		c.-64+552C>T		intron	N/A	NP_001305123.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTHL1	ENST00000651570.2	MANE Select	c.115+552C>T		intron	N/A	ENSP00000498421.1	P78549-2
	NTHL1	ENST00000219066.5	TSL:1	c.139+552C>T		intron	N/A	ENSP00000219066.1	P78549-1
	NTHL1	ENST00000925707.1		c.115+552C>T		intron	N/A	ENSP00000595766.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44781 AN: 152006 Hom.: 8160 Cov.: 33

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.174 AC: 560 AN: 3216 Hom.: 56 Cov.: 0 AF XY: 0.170 AC XY: 293 AN XY: 1720

African (AFR) AF: 0.458 AC: 11 AN: 24

American (AMR) AF: 0.112 AC: 23 AN: 206

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 7 AN: 42

East Asian (EAS) AF: 0.0294 AC: 1 AN: 34

South Asian (SAS) AF: 0.131 AC: 78 AN: 594

European-Finnish (FIN) AF: 0.194 AC: 21 AN: 108

Middle Eastern (MID) AF: 0.167 AC: 3 AN: 18

European-Non Finnish (NFE) AF: 0.193 AC: 397 AN: 2060

Other (OTH) AF: 0.146 AC: 19 AN: 130

GnomAD4 genome AF: 0.295 AC: 44857 AN: 152124 Hom.: 8187 Cov.: 33 AF XY: 0.292 AC XY: 21698 AN XY: 74358

African (AFR) AF: 0.515 AC: 21336 AN: 41464

American (AMR) AF: 0.235 AC: 3601 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3470

East Asian (EAS) AF: 0.0222 AC: 115 AN: 5182

South Asian (SAS) AF: 0.124 AC: 599 AN: 4830

European-Finnish (FIN) AF: 0.241 AC: 2547 AN: 10582

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14779 AN: 67984

Other (OTH) AF: 0.283 AC: 598 AN: 2110

Alfa AF: 0.241 Hom.: 18752

Bravo AF: 0.305

Asia WGS AF: 0.104 AC: 363 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.49
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs2516739; hg19: chr16-2097158;