Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014159.7(SETD2):c.664C>A(p.Leu222Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,551,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.45

Publications

0 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:

ENSG00000296084 (HGNC:):

ENSG00000296084 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024086446).

BP6

Variant 3-47123972-G-T is Benign according to our data. Variant chr3-47123972-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475534.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000328 (50/152324) while in subpopulation AFR AF = 0.00113 (47/41576). AF 95% confidence interval is 0.000873. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETD2	NM_014159.7	MANE Select	c.664C>A	p.Leu222Ile	missense	Exon 3 of 21	NP_054878.5
SETD2	NM_001349370.3		c.532C>A	p.Leu178Ile	missense	Exon 2 of 20	NP_001336299.1
SETD2	NR_146158.3		n.853C>A		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SETD2	ENST00000409792.4	TSL:5 MANE Select	c.664C>A	p.Leu222Ile	missense	Exon 3 of 21	ENSP00000386759.3
SETD2	ENST00000330022.11	TSL:1	n.277C>A		non_coding_transcript_exon	Exon 1 of 19	ENSP00000332415.7
SETD2	ENST00000638947.2	TSL:5	c.532C>A	p.Leu178Ile	missense	Exon 2 of 20	ENSP00000491413.2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000819

AC:

AN:

158742

AF XY:

0.0000718

show subpopulations

Gnomad AFR exome

AF:

0.00132

Gnomad AMR exome

AF:

0.0000807

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:

0.0000343

AC:

AN:

1398928

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

690042

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

31588

American (AMR)

AF:

0.0000560

AC:

AN:

35710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1078104

Other (OTH)

AF:

0.000103

AC:

AN:

58156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41576

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000656

Hom.:

Bravo

AF:

0.000370

ExAC

AF:

0.0000366

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Luscan-Lumish syndrome (1)

Luscan-Lumish syndrome;C5774269:Rabin-Pappas syndrome;C5774271:Intellectual developmental disorder, autosomal dominant 70 (1)

SETD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.17

Eigen

Benign

-0.020

Eigen_PC

Benign

0.022

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

M_CAP

Benign

0.037

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.81

PhyloP100

3.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.14

REVEL

Benign

0.11

Sift

Benign

0.12

Sift4G

Benign

0.16

Polyphen

0.89

Vest4

0.13

MVP

0.35

MPC

0.48

ClinPred

0.057

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.13

Mutation Taster

=79/21

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over