chr3-47121932-C-G

Position:

• chr3-47121932-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_014159.7(SETD2):​c.2704G>C​(p.Glu902Gln) variant causes a missense change. The variant allele was found at a frequency of 0.012 in 1,613,906 control chromosomes in the GnomAD database, including 1,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (1026 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (956 hom.)
• Consequence: SETD2 NM_014159.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 4.82

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 -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015663505).
• BP6: Variant 3-47121932-C-G is Benign according to our data. Variant chr3-47121932-C-G is described in ClinVar as [Benign]. Clinvar id is 135230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-47121932-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7	c.2704G>C	p.Glu902Gln	missense_variant	3/21	ENST00000409792.4	NP_054878.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4	c.2704G>C	p.Glu902Gln	missense_variant	3/21	5	NM_014159.7	ENSP00000386759.3

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9617 AN: 152116 Hom.: 1020 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0167 AC: 4186 AN: 250786 Hom.: 452 AF XY: 0.0124 AC XY: 1686 AN XY: 135592

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000565

Gnomad OTH exome AF: 0.00868

GnomAD4 exome AF: 0.00662 AC: 9674 AN: 1461672 Hom.: 956 Cov.: 34 AF XY: 0.00571 AC XY: 4149 AN XY: 727130

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0633 AC: 9637 AN: 152234 Hom.: 1026 Cov.: 32 AF XY: 0.0603 AC XY: 4489 AN XY: 74426

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.0307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.00480 Hom.: 41

Bravo AF: 0.0738

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.209 AC: 923

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0203 AC: 2466

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Luscan-Lumish syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.040	D;.
Polyphen		0.98	D;.
Vest4		0.046
MPC		0.44
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.39

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: rs58906143; hg19: chr3-47163422;