rs4082155

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_014159.7(SETD2):c.5885C>T(p.Pro1962Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,613,586 control chromosomes in the GnomAD database, including 252,442 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 19246 hom., cov: 32)

Exomes 𝑓: 0.56 ( 233196 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.296

Variant links:

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 links:

SETD2 (HGNC:):

SETD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=8.802437E-6).

BP6

Variant 3-47083895-G-A is Benign according to our data. Variant chr3-47083895-G-A is described in ClinVar as [Benign]. Clinvar id is 135202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7 linkuse as main transcript	c.5885C>T	p.Pro1962Leu	missense_variant	12/21	ENST00000409792.4	NP_054878.5	Q9BYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4 linkuse as main transcript	c.5885C>T	p.Pro1962Leu	missense_variant	12/21	5	NM_014159.7	ENSP00000386759.3		Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.484

AC:

73489

AN:

151800

Hom.:

19232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.487

Gnomad ASJ

AF:

0.519

Gnomad EAS

AF:

0.551

Gnomad SAS

AF:

0.547

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.576

Gnomad OTH

AF:

0.493

GnomAD3 exomes

AF:

0.538

AC:

135242

AN:

251370

Hom.:

37288

AF XY:

0.543

AC XY:

73702

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.280

Gnomad AMR exome

AF:

0.502

Gnomad ASJ exome

AF:

0.520

Gnomad EAS exome

AF:

0.542

Gnomad SAS exome

AF:

0.545

Gnomad FIN exome

AF:

0.614

Gnomad NFE exome

AF:

0.570

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.562

AC:

821135

AN:

1461668

Hom.:

233196

Cov.:

AF XY:

0.561

AC XY:

408136

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.275

Gnomad4 AMR exome

AF:

0.499

Gnomad4 ASJ exome

AF:

0.516

Gnomad4 EAS exome

AF:

0.563

Gnomad4 SAS exome

AF:

0.545

Gnomad4 FIN exome

AF:

0.606

Gnomad4 NFE exome

AF:

0.575

Gnomad4 OTH exome

AF:

0.544

GnomAD4 genome

AF:

0.484

AC:

73533

AN:

151918

Hom.:

19246

Cov.:

AF XY:

0.485

AC XY:

35965

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.488

Gnomad4 ASJ

AF:

0.519

Gnomad4 EAS

AF:

0.551

Gnomad4 SAS

AF:

0.547

Gnomad4 FIN

AF:

0.614

Gnomad4 NFE

AF:

0.576

Gnomad4 OTH

AF:

0.496

Alfa

AF:

0.545

Hom.:

47732

Bravo

AF:

0.465

TwinsUK

AF:

0.558

AC:

2070

ALSPAC

AF:

0.584

AC:

2249

ESP6500AA

AF:

0.286

AC:

1261

ESP6500EA

AF:

0.566

AC:

4869

ExAC

AF:

0.534

AC:

64850

Asia WGS

AF:

0.592

AC:

2057

AN:

3478

EpiCase

AF:

0.551

EpiControl

AF:

0.555

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Luscan-Lumish syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.063

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0000088

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.30

N;.

REVEL

Benign

0.033

Sift

Benign

0.31

T;.

Sift4G

Benign

0.22

T;.

Polyphen

0.0

B;.

Vest4

0.035

MPC

0.56

ClinPred

0.0038

GERP RS

2.9

Varity_R

0.027

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over