6-31900627-C-T

Variant summary

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

The NM_181842.3(ZBTB12):​c.679G>A​(p.Gly227Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,612,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

ZBTB12
NM_181842.3 missense

Scores

5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00
Variant links:
Genes affected
ZBTB12 (HGNC:19066): (zinc finger and BTB domain containing 12) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]
C2 (HGNC:1248): (complement C2) Component C2 is a serum glycoprotein that functions as part of the classical pathway of the complement system. Activated C1 cleaves C2 into C2a and C2b. The serine proteinase C2a then combines with complement factor 4b to create the C3 or C5 convertase. Deficiency of C2 has been reported to associated with certain autoimmune diseases and SNPs in this gene have been associated with altered susceptibility to age-related macular degeneration. This gene localizes within the class III region of the MHC on the short arm of chromosome 6. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described in publications but their full-length sequence has not been determined.[provided by RefSeq, Mar 2009]

Genome browser will be placed here

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=0.17274535).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZBTB12NM_181842.3 linkc.679G>A p.Gly227Arg missense_variant Exon 2 of 2 ENST00000375527.3 NP_862825.1 Q9Y330
C2NM_001282457.2 linkc.-64+2685C>T intron_variant Intron 1 of 13 NP_001269386.1 B4DQI1Q53HP3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZBTB12ENST00000375527.3 linkc.679G>A p.Gly227Arg missense_variant Exon 2 of 2 1 NM_181842.3 ENSP00000364677.2 Q9Y330
C2ENST00000695637.1 linkc.-360+2352C>T intron_variant Intron 1 of 17 ENSP00000512074.1 A0A8Q3WKN5
C2ENST00000497706.6 linkc.-64+2685C>T intron_variant Intron 1 of 14 5 ENSP00000417482.2 E9PDZ0
C2ENST00000469372.5 linkc.-64+2685C>T intron_variant Intron 1 of 13 2 ENSP00000418923.1 B4DQI1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152238
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000203
AC:
5
AN:
246068
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134144
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000453
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000575
AC:
84
AN:
1460440
Hom.:
0
Cov.:
58
AF XY:
0.0000523
AC XY:
38
AN XY:
726544
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:
0.0000728
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000451
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000168
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.679G>A (p.G227R) alteration is located in exon 2 (coding exon 1) of the ZBTB12 gene. This alteration results from a G to A substitution at nucleotide position 679, causing the glycine (G) at amino acid position 227 to be replaced by an arginine (R). 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
Uncertain
0.37
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0041
T
Eigen
Benign
-0.061
Eigen_PC
Benign
-0.011
FATHMM_MKL
Uncertain
0.86
D
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.6
L
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.55
N
REVEL
Benign
0.035
Sift
Benign
0.41
T
Sift4G
Benign
0.55
T
Polyphen
0.82
P
Vest4
0.16
MutPred
0.31
Gain of solvent accessibility (P = 0.019);
MVP
0.082
MPC
2.5
ClinPred
0.35
T
GERP RS
3.8
Varity_R
0.13
gMVP
0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201121876; hg19: chr6-31868404; API