rs2290547

Positions:

• chr3-47019693-G-A
• chr3-47019693-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014159.7(SETD2):​c.7431+67C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,330,376 control chromosomes in the GnomAD database, including 18,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1823 hom., cov: 32)
  • Exomes 𝑓: 0.16 (16907 hom.)
• Consequence: SETD2 NM_014159.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.120

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]

SETD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-47019693-G-A is Benign according to our data. Variant chr3-47019693-G-A is described in ClinVar as [Benign]. Clinvar id is 1221230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7	c.7431+67C>T		intron_variant		ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.7431+67C>T		intron_variant		5	NM_014159.7	ENSP00000386759.3

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20583 AN: 152032 Hom.: 1822 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0981

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.155

GnomAD4 exome AF: 0.163 AC: 192473 AN: 1178224 Hom.: 16907 AF XY: 0.161 AC XY: 96509 AN XY: 599222

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.0910

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.0939

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.135 AC: 20575 AN: 152152 Hom.: 1823 Cov.: 32 AF XY: 0.138 AC XY: 10238 AN XY: 74366

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.0981

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.0912

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.153

Alfa AF: 0.144 Hom.: 1167

Bravo AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs2290547; hg19: chr3-47061183; COSMIC: COSV57433242;