rs1244929991

Positions:

• chr3-47062337-C-A
• chr3-47062337-C-G
• chr3-47062337-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014159.7(SETD2):​c.6119G>T​(p.Arg2040Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,668 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SETD2. . Gene score misZ 3.0459 (greater than the threshold 3.09). Trascript score misZ 4.1385 (greater than threshold 3.09). GenCC has associacion of gene with SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, Luscan-Lumish syndrome, Rabin-Pappas syndrome, SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome, Sotos syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7	c.6119G>T	p.Arg2040Leu	missense_variant	14/21	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.6119G>T	p.Arg2040Leu	missense_variant	14/21	5	NM_014159.7	ENSP00000386759	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441668 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.29		Gain of glycosylation at T2036 (P = 0.0522);
MVP		0.73
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr3-47103827;