ENST00000695637.1:c.-360+1201C>T

Variant names:

• chr6-31899476-C-T
• rs9267663
• ENST00000695637.1:c.-360+1201C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000695637.1(C2):​c.-360+1201C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0694 in 166,388 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.074 (642 hom., cov: 27)
  • Exomes 𝑓: 0.025 (18 hom.)
• Consequence: C2 ENST00000695637.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• Publications: 10 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_001282457.2	c.-64+1534C>T		intron_variant	Intron 1 of 13		NP_001269386.1
ZBTB12	NM_181842.3	c.*450G>A		downstream_gene_variant		ENST00000375527.3	NP_862825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000695637.1	c.-360+1201C>T		intron_variant	Intron 1 of 17			ENSP00000512074.1
C2	ENST00000497706.6	c.-64+1534C>T		intron_variant	Intron 1 of 14	5		ENSP00000417482.2
C2	ENST00000469372.5	c.-64+1534C>T		intron_variant	Intron 1 of 13	2		ENSP00000418923.1
ZBTB12	ENST00000375527.3	c.*450G>A		downstream_gene_variant		1	NM_181842.3	ENSP00000364677.2

Frequencies

GnomAD3 genomes AF: 0.0737 AC: 11171 AN: 151676 Hom.: 643 Cov.: 27

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.00492

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0247 AC: 360 AN: 14592 Hom.: 18 AF XY: 0.0261 AC XY: 193 AN XY: 7394

African (AFR) AF: 0.109 AC: 38 AN: 348

American (AMR) AF: 0.0481 AC: 62 AN: 1290

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 20 AN: 470

East Asian (EAS) AF: 0.00292 AC: 2 AN: 684

South Asian (SAS) AF: 0.0643 AC: 31 AN: 482

European-Finnish (FIN) AF: 0.00258 AC: 1 AN: 388

Middle Eastern (MID) AF: 0.0625 AC: 4 AN: 64

European-Non Finnish (NFE) AF: 0.0179 AC: 180 AN: 10036

Other (OTH) AF: 0.0265 AC: 22 AN: 830

GnomAD4 genome AF: 0.0737 AC: 11180 AN: 151796 Hom.: 642 Cov.: 27 AF XY: 0.0723 AC XY: 5365 AN XY: 74210

African (AFR) AF: 0.144 AC: 5933 AN: 41270

American (AMR) AF: 0.0860 AC: 1309 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 404 AN: 3466

East Asian (EAS) AF: 0.0511 AC: 264 AN: 5164

South Asian (SAS) AF: 0.104 AC: 500 AN: 4800

European-Finnish (FIN) AF: 0.00492 AC: 52 AN: 10576

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0362 AC: 2462 AN: 67990

Other (OTH) AF: 0.104 AC: 220 AN: 2112

Alfa AF: 0.0495 Hom.: 801

Bravo AF: 0.0827

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.92
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9267663; hg19: chr6-31867253;