chr3-47123960-G-C

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

1
18

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 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

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 id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SETD2NM_014159.7 linkc.676C>G p.Pro226Ala missense_variant Exon 3 of 21 ENST00000409792.4 NP_054878.5 Q9BYW2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SETD2ENST00000409792.4 linkc.676C>G p.Pro226Ala missense_variant Exon 3 of 21 5 NM_014159.7 ENSP00000386759.3 Q9BYW2-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152232
Hom.:
0
Cov.:
32
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:
2
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:
41
AN:
1398390
Hom.:
0
Cov.:
32
AF XY:
0.0000275
AC XY:
19
AN XY:
689788
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31566
American (AMR)
AF:
0.00
AC:
0
AN:
35708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25162
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35734
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79200
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49510
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5698
European-Non Finnish (NFE)
AF:
0.0000362
AC:
39
AN:
1077714
Other (OTH)
AF:
0.0000344
AC:
2
AN:
58098
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
3
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74380
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68044
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000227
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Luscan-Lumish syndrome Benign:1Other:1
-
GenomeConnect - Brain Gene Registry
Significance:not provided
Review Status:no classification provided
Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 07-01-2019 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Feb 03, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
17
DANN
Benign
0.90
DEOGEN2
Benign
0.28
T;T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.17
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.68
T;T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
0.55
N;.
PhyloP100
2.0
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.93
N;N
REVEL
Benign
0.051
Sift
Benign
0.031
D;T
Sift4G
Benign
0.15
T;.
Polyphen
0.24
B;.
Vest4
0.26
MutPred
0.33
Loss of sheet (P = 0.0025);.;
MVP
0.34
MPC
0.68
ClinPred
0.10
T
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

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

Other links and lift over

dbSNP: rs780963440; hg19: chr3-47165450; API