NM_181842.3:c.129G>C

Variant names:

• chr6-31901177-C-G
• NM_181842.3:c.129G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181842.3(ZBTB12):​c.129G>C​(p.Lys43Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZBTB12 NM_181842.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32925725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB12	NM_181842.3	c.129G>C	p.Lys43Asn	missense_variant	Exon 2 of 2	ENST00000375527.3	NP_862825.1
C2	NM_001178063.3	c.73+38C>G		intron_variant	Intron 1 of 13		NP_001171534.1
C2	NM_001282457.2	c.-64+3235C>G		intron_variant	Intron 1 of 13		NP_001269386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB12	ENST00000375527.3	c.129G>C	p.Lys43Asn	missense_variant	Exon 2 of 2	1	NM_181842.3	ENSP00000364677.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.129G>C (p.K43N) alteration is located in exon 2 (coding exon 1) of the ZBTB12 gene. This alteration results from a G to C substitution at nucleotide position 129, causing the lysine (K) at amino acid position 43 to be replaced by an asparagine (N). 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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.043	D
Polyphen		0.82	P
Vest4		0.25
MutPred		0.51		Loss of methylation at K43 (P = 0.013);
MVP		0.32
MPC		2.2
ClinPred		0.89	D
GERP RS		3.6
Varity_R		0.085
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31868954;