rs4082155

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1962H) has been classified as Uncertain significance.

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

Publications

80 publications found

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 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

SETD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId 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 rank	MANE	Protein	UniProt
SETD2	NM_014159.7 link	c.5885C>T	p.Pro1962Leu	missense_variant	Exon 12 of 21	ENST00000409792.4	NP_054878.5	Q9BYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD2	ENST00000409792.4 link	c.5885C>T	p.Pro1962Leu	missense_variant	Exon 12 of 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

GnomAD2 exomes

AF:

0.538

AC:

135242

AN:

251370

AF XY:

0.543

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 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

African (AFR)

AF:

0.275

AC:

9204

AN:

33470

American (AMR)

AF:

0.499

AC:

22320

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.516

AC:

13483

AN:

26130

East Asian (EAS)

AF:

0.563

AC:

22340

AN:

39696

South Asian (SAS)

AF:

0.545

AC:

47030

AN:

86254

European-Finnish (FIN)

AF:

0.606

AC:

32347

AN:

53406

Middle Eastern (MID)

AF:

0.457

AC:

2634

AN:

5768

European-Non Finnish (NFE)

AF:

0.575

AC:

638909

AN:

1111830

Other (OTH)

AF:

0.544

AC:

32868

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

22269

44538

66806

89075

111344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17582

35164

52746

70328

87910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.484

AC:

73533

AN:

151918

Hom.:

19246

Cov.:

AF XY:

0.485

AC XY:

35965

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.281

AC:

11635

AN:

41410

American (AMR)

AF:

0.488

AC:

7441

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.519

AC:

1802

AN:

3470

East Asian (EAS)

AF:

0.551

AC:

2841

AN:

5152

South Asian (SAS)

AF:

0.547

AC:

2636

AN:

4820

European-Finnish (FIN)

AF:

0.614

AC:

6478

AN:

10542

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.576

AC:

39146

AN:

67952

Other (OTH)

AF:

0.496

AC:

1046

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1786

3572

5357

7143

8929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.532

Hom.:

69560

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Luscan-Lumish syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

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

(source)

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;.

PhyloP100

0.30

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

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over