rs77310684

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_014159.7(SETD2):c.578C>T(p.Pro193Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0007 in 1,551,882 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 19 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.27

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=0.0076925457).

BP6

Variant 3-47124058-G-A is Benign according to our data. Variant chr3-47124058-G-A is described in ClinVar as [Benign]. Clinvar id is 475527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000525 (80/152236) while in subpopulation EAS AF= 0.0137 (71/5174). AF 95% confidence interval is 0.0112. There are 2 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD2	NM_014159.7 linkuse as main transcript	c.578C>T	p.Pro193Leu	missense_variant	3/21	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.578C>T	p.Pro193Leu	missense_variant	3/21	5	NM_014159.7	ENSP00000386759.3		Q9BYW2-1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000951

AC:

150

AN:

157722

Hom.:

AF XY:

0.000888

AC XY:

AN XY:

83318

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0115

Gnomad SAS exome

AF:

0.000527

Gnomad FIN exome

AF:

0.0000592

Gnomad NFE exome

AF:

0.0000326

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000719

AC:

1006

AN:

1399646

Hom.:

Cov.:

AF XY:

0.000697

AC XY:

481

AN XY:

690326

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0257

Gnomad4 SAS exome

AF:

0.000467

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.0000195

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.000526

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0137

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000529

ExAC

AF:

0.000730

AC:

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Luscan-Lumish syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

SETD2: BP4, BS1, BS2 -

SETD2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0077

T;T

MetaSVM

Uncertain

-0.080

MutationAssessor

Benign

1.1

L;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

N;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.46

MVP

0.70

MPC

0.92

ClinPred

0.058

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.32

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