rs2290547

Variant names:

• chr3-47019693-G-A
• rs2290547
• NM_014159.7:c.7431+67C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• Luscan-Lumish syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Rabin-Pappas syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• Sotos syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual developmental disorder, autosomal dominant 70

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SETD2	NM_014159.7	c.7431+67C>T		intron_variant	Intron 19 of 20	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.7431+67C>T		intron_variant	Intron 19 of 20	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

African (AFR) AF: 0.0282 AC: 785 AN: 27832

American (AMR) AF: 0.122 AC: 5372 AN: 43878

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 2200 AN: 24178

East Asian (EAS) AF: 0.220 AC: 8389 AN: 38182

South Asian (SAS) AF: 0.0939 AC: 7511 AN: 80020

European-Finnish (FIN) AF: 0.235 AC: 12418 AN: 52900

Middle Eastern (MID) AF: 0.126 AC: 657 AN: 5194

European-Non Finnish (NFE) AF: 0.172 AC: 147233 AN: 855052

Other (OTH) AF: 0.155 AC: 7908 AN: 50988

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

African (AFR) AF: 0.0332 AC: 1381 AN: 41540

American (AMR) AF: 0.148 AC: 2266 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 340 AN: 3466

East Asian (EAS) AF: 0.228 AC: 1181 AN: 5174

South Asian (SAS) AF: 0.0912 AC: 439 AN: 4816

European-Finnish (FIN) AF: 0.243 AC: 2566 AN: 10548

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11894 AN: 67998

Other (OTH) AF: 0.153 AC: 324 AN: 2114

Alfa AF: 0.142 Hom.: 1617

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		0.12
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: rs2290547; hg19: chr3-47061183; COSMIC: COSV57433242;