rs139628048

chr3-47057329-T-Achr3-47057329-T-Cchr3-47057329-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014159.7(SETD2):c.6455A>T(p.Tyr2152Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2152C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32

Genes affected

SETD2 (HGNC:18420): (SET domain containing 2, histone lysine methyltransferase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SETD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.13089517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD2	NM_014159.7	c.6455A>T	p.Tyr2152Phe	missense_variant	15/21	ENST00000409792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD2	ENST00000409792.4	c.6455A>T	p.Tyr2152Phe	missense_variant	15/21	5	NM_014159.7	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.022
Sift	Benign	0.16	T
Sift4G	Benign	0.37	T
Polyphen		0.018	B
Vest4		0.29
MutPred		0.20		Gain of glycosylation at Y2152 (P = 0.0011);
MVP		0.38
MPC		0.52
ClinPred		0.30	T
GERP RS		4.1
Varity_R		0.061
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-47098819; COSMIC: COSV105212407; COSMIC: COSV105212407;