6-31901066-G-A

Position:

• chr6-31901066-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_181842.3(ZBTB12):​c.240C>T​(p.Ile80Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,614,196 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0096 (22 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (17 hom.)
• Consequence: ZBTB12 NM_181842.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.12

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 6-31901066-G-A is Benign according to our data. Variant chr6-31901066-G-A is described in ClinVar as [Benign]. Clinvar id is 3038897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00962 (1465/152342) while in subpopulation AFR AF= 0.0305 (1270/41572). AF 95% confidence interval is 0.0292. There are 22 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB12	NM_181842.3	c.240C>T	p.Ile80Ile	synonymous_variant	2/2	ENST00000375527.3	NP_862825.1
C2	NM_001178063.3	c.-1G>A		5_prime_UTR_variant	1/14		NP_001171534.1
C2	NM_001282457.2	c.-64+3124G>A		intron_variant			NP_001269386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB12	ENST00000375527.3	c.240C>T	p.Ile80Ile	synonymous_variant	2/2	1	NM_181842.3	ENSP00000364677.2

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152224 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00296 AC: 744 AN: 251286 Hom.: 7 AF XY: 0.00223 AC XY: 303 AN XY: 135868

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000784

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00138 AC: 2023 AN: 1461854 Hom.: 17 Cov.: 37 AF XY: 0.00126 AC XY: 919 AN XY: 727228

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000595

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.00962 AC: 1465 AN: 152342 Hom.: 22 Cov.: 31 AF XY: 0.00969 AC XY: 722 AN XY: 74490

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00429 Hom.: 1

Bravo AF: 0.0106

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

C2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

ZBTB12-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.6
DANN	Benign	0.94

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

Other links and lift over

dbSNP: rs148838488; hg19: chr6-31868843;