Genetic Variant NM_014159.7:c.676C>G (chr3-47123960-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_014159.7(SETD2):c.676C>G(p.Pro226Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,550,622 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SETD2
NM_014159.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 1.96

Publications

2 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, STRONG Submitted by: PanelApp Australia, ClinGen
Rabin-Pappas syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13133606).

BP6

Variant 3-47123960-G-C is Benign according to our data. Variant chr3-47123960-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 542220.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000293 (41/1398390) while in subpopulation NFE AF = 0.0000362 (39/1077714). AF 95% confidence interval is 0.0000271. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 41 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	UniProt
SETD2	NM_014159.7	MANE Select	c.676C>G	p.Pro226Ala	missense	Exon 3 of 21	NP_054878.5
SETD2	NM_001349370.3		c.544C>G	p.Pro182Ala	missense	Exon 2 of 20	NP_001336299.1	A0A1W2PPX9
SETD2	NR_146158.3		n.865C>G		non_coding_transcript_exon	Exon 3 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD2	ENST00000409792.4	TSL:5 MANE Select	c.676C>G	p.Pro226Ala	missense	Exon 3 of 21	ENSP00000386759.3	Q9BYW2-1
SETD2	ENST00000330022.11	TSL:1	n.289C>G		non_coding_transcript_exon	Exon 1 of 19	ENSP00000332415.7	H7BXT4
SETD2	ENST00000952253.1		c.676C>G	p.Pro226Ala	missense	Exon 3 of 20	ENSP00000622312.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

158504

AF XY:

0.0000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000324

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1398390

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

689788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31566

American (AMR)

AF:

0.00

AC:

AN:

35708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25162

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000362

AC:

AN:

1077714

Other (OTH)

AF:

0.0000344

AC:

AN:

58098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000282

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Luscan-Lumish syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.28

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.68

M_CAP

Benign

0.059

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.55

PhyloP100

2.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.93

REVEL

Benign

0.051

Sift

Benign

0.031

Sift4G

Benign

0.15

Polyphen

0.24

Vest4

0.26

MutPred

0.33

Loss of sheet (P = 0.0025)

MVP

0.34

MPC

0.68

ClinPred

0.10

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.16

Mutation Taster

=91/9

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

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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

Computational scores

Splicing

Publications

Other links and lift over