6-31935916-C-T

Variant names:

• chr6-31935916-C-T
• rs151097610
• NM_000063.6:c.850-7C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000063.6(C2):​c.850-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000887 in 1,612,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: C2 NM_000063.6 splice_region, intron
• Scores: Splicing: ADA: 0.0008368
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0200

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]

ENSG00000244255 (HGNC:):

C2-AS1 (HGNC:49464): (C2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-31935916-C-T is Benign according to our data. Variant chr6-31935916-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1087273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000302 (46/152230) while in subpopulation AFR AF= 0.000963 (40/41520). AF 95% confidence interval is 0.000727. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_000063.6	c.850-7C>T		splice_region_variant, intron_variant	Intron 6 of 17	ENST00000299367.10	NP_000054.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000299367.10	c.850-7C>T		splice_region_variant, intron_variant	Intron 6 of 17	1	NM_000063.6	ENSP00000299367.5
ENSG00000244255	ENST00000456570.5	c.530-1403C>T		intron_variant	Intron 4 of 29	2		ENSP00000410815.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152112 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000101 AC: 25 AN: 246844 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134478

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000631

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1460656 Hom.: 0 Cov.: 31 AF XY: 0.0000716 AC XY: 52 AN XY: 726648

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152230 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21 AN XY: 74436

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.5
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00084
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.040		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: rs151097610; hg19: chr6-31903693;