chr3-47121860-T-C

Variant names:

• chr3-47121860-T-C
• rs1167396235
• NM_014159.7:c.2776A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_014159.7(SETD2):​c.2776A>G​(p.Lys926Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.231
• Publications: 2 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

ENSG00000296084 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082069516).
• BP6: Variant 3-47121860-T-C is Benign according to our data. Variant chr3-47121860-T-C is described in ClinVar as Benign. ClinVar VariationId is 475504.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	NM_014159.7	MANE Select	c.2776A>G	p.Lys926Glu	missense	Exon 3 of 21	NP_054878.5
	SETD2	NM_001349370.3		c.2644A>G	p.Lys882Glu	missense	Exon 2 of 20	NP_001336299.1
	SETD2	NR_146158.3		n.2965A>G		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD2	ENST00000409792.4	TSL:5 MANE Select	c.2776A>G	p.Lys926Glu	missense	Exon 3 of 21	ENSP00000386759.3
	SETD2	ENST00000330022.11	TSL:1	n.2389A>G		non_coding_transcript_exon	Exon 1 of 19	ENSP00000332415.7
	SETD2	ENST00000952253.1		c.2776A>G	p.Lys926Glu	missense	Exon 3 of 20	ENSP00000622312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250722 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Luscan-Lumish syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.23
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.12
Sift	Benign	0.29	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.12		Loss of ubiquitination at K926 (P = 0.002)
MVP		0.65
MPC		0.35
ClinPred		0.033	T
GERP RS		2.5
PromoterAI		0.013	Neutral
Varity_R		0.059
gMVP		0.45
Mutation Taster		=97/3	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: rs1167396235; hg19: chr3-47163350;