3-47046492-G-T

Variant names:

• chr3-47046492-G-T
• rs894915057
• NM_014159.7:c.7093C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014159.7(SETD2):​c.7093C>A​(p.Gln2365Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. Q2365E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3631991).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014159.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.7093C>A	p.Gln2365Lys	missense	Exon 16 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.6961C>A	p.Gln2321Lys	missense	Exon 15 of 20	NP_001336299.1
	SETD2	NR_146158.3		n.7450C>A		non_coding_transcript_exon	Exon 17 of 22

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.7093C>A	p.Gln2365Lys	missense	Exon 16 of 21	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.*2816C>A		non_coding_transcript_exon	Exon 14 of 19	ENSP00000332415.7
	SETD2	ENST00000330022.11	TSL:1	n.*2816C>A		3_prime_UTR	Exon 14 of 19	ENSP00000332415.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443370 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718186

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 42364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25666

East Asian (EAS) AF: 0.00 AC: 0 AN: 39166

South Asian (SAS) AF: 0.00 AC: 0 AN: 83268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102172

Other (OTH) AF: 0.00 AC: 0 AN: 59342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.97	L
PhyloP100		8.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.78	P
Vest4		0.45
MutPred		0.20		Gain of ubiquitination at Q2365 (P = 0.0042)
MVP		0.81
MPC		1.7
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.18
gMVP		0.42
Mutation Taster		=56/44	polymorphism

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: rs894915057; hg19: chr3-47087982;