rs45517156

Variant names:

• chr16-2061970-T-C
• NM_000548.5:c.1219T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2061970-T-C
• chr16-2061970-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000548.5(TSC2):​c.1219T>C​(p.Tyr407His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y407D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37

Genes affected

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2061970-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1219T>C	p.Tyr407His	missense_variant	Exon 12 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1219T>C	p.Tyr407His	missense_variant	Exon 12 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y407H variant (also known as c.1219T>C), located in coding exon 11 of the TSC2 gene, results from a T to C substitution at nucleotide position 1219. The tyrosine at codon 407 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.98	D;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4		0.71
MutPred		0.69		Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);.;Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);.;Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);.;
MVP		0.64
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2111971;