rs4752

Positions:

• chr4-71756849-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000583.4(GC):​c.897T>C​(p.Cys299=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,362 control chromosomes in the GnomAD database, including 2,966 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 0.083 (1293 hom., cov: 33)
  • Exomes 𝑓: 0.016 (1673 hom.)
• Consequence: GC NM_000583.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.307

Genes affected

GC (HGNC:4187): (GC vitamin D binding protein) The protein encoded by this gene belongs to the albumin gene family. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=0.307 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GC	NM_000583.4	c.897T>C	p.Cys299=	synonymous_variant	8/13	ENST00000273951.13	NP_000574.2
GC	NM_001204307.1	c.954T>C	p.Cys318=	synonymous_variant	9/14		NP_001191236.1
GC	NM_001204306.1	c.897T>C	p.Cys299=	synonymous_variant	9/14		NP_001191235.1
GC	XM_006714177.3	c.897T>C	p.Cys299=	synonymous_variant	8/12		XP_006714240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13	c.897T>C	p.Cys299=	synonymous_variant	8/13	1	NM_000583.4	ENSP00000273951	P1

Frequencies

GnomAD3 genomes AF: 0.0830 AC: 12614 AN: 152054 Hom.: 1290 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0860

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.0741

GnomAD3 exomes AF: 0.0384 AC: 9643 AN: 251256 Hom.: 656 AF XY: 0.0317 AC XY: 4310 AN XY: 135788

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.0726

Gnomad SAS exome AF: 0.00552

Gnomad FIN exome AF: 0.0538

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0164 AC: 23938 AN: 1461190 Hom.: 1673 Cov.: 31 AF XY: 0.0152 AC XY: 11021 AN XY: 726948

Gnomad4 AFR exome AF: 0.256

Gnomad4 AMR exome AF: 0.0575

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.00558

Gnomad4 FIN exome AF: 0.0523

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.0301

GnomAD4 genome AF: 0.0830 AC: 12636 AN: 152172 Hom.: 1293 Cov.: 33 AF XY: 0.0838 AC XY: 6230 AN XY: 74386

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.0640

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0855

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.00423

Gnomad4 OTH AF: 0.0743

Alfa AF: 0.0240 Hom.: 450

Bravo AF: 0.0923

Asia WGS AF: 0.0700 AC: 241 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00492

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.0
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4752; hg19: chr4-72622566; COSMIC: COSV56737625; COSMIC: COSV56737625;