6-73440233-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138441.3(CGAS):​c.1090G>A​(p.Ala364Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CGAS
NM_138441.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56
Variant links:
Genes affected
CGAS (HGNC:21367): (cyclic GMP-AMP synthase) Enables several functions, including 2',3'-cyclic GMP-AMP synthase activity; chromatin binding activity; and phosphatidylinositol-4,5-bisphosphate binding activity. Involved in several processes, including cellular response to exogenous dsRNA; positive regulation of intracellular signal transduction; and regulation of defense response. Located in several cellular components, including cytosol; nucleus; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2609769).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CGASNM_138441.3 linkc.1090G>A p.Ala364Thr missense_variant 3/5 ENST00000370315.4 NP_612450.2 Q8N884-1
CGASNM_001410911.1 linkc.1090G>A p.Ala364Thr missense_variant 3/6 NP_001397840.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CGASENST00000370315.4 linkc.1090G>A p.Ala364Thr missense_variant 3/51 NM_138441.3 ENSP00000359339.3 Q8N884-1
CGASENST00000370318.5 linkc.1090G>A p.Ala364Thr missense_variant 3/61 ENSP00000359342.1 Q8N884-2
CGASENST00000680833.1 linkc.1090G>A p.Ala364Thr missense_variant 3/6 ENSP00000506638.1 A0A7P0TBQ3
CGASENST00000459924.1 linkn.371G>A non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459932
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726054
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 22, 2024The c.1090G>A (p.A364T) alteration is located in exon 3 (coding exon 3) of the MB21D1 gene. This alteration results from a G to A substitution at nucleotide position 1090, causing the alanine (A) at amino acid position 364 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0090
.;T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.79
T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.26
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M;M
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.17
Sift
Benign
0.068
T;T
Sift4G
Benign
0.52
T;T
Polyphen
0.96
.;D
Vest4
0.20
MVP
0.40
MPC
0.76
ClinPred
0.85
D
GERP RS
5.3
Varity_R
0.20
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1287076884; hg19: chr6-74149956; API