rs4752

Variant names:

• chr4-71756849-A-G
• rs4752
• NM_000583.4:c.897T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000583.4(GC):​c.897T>C​(p.Cys299Cys) 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
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GC	NM_000583.4	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 8 of 13	ENST00000273951.13	NP_000574.2
GC	NM_001204307.1	c.954T>C	p.Cys318Cys	synonymous_variant	Exon 9 of 14		NP_001191236.1
GC	NM_001204306.1	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 9 of 14		NP_001191235.1
GC	NM_001440458.1	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 8 of 12		NP_001427387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 8 of 13	1	NM_000583.4	ENSP00000273951.8

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

GnomAD2 exomes AF: 0.0384 AC: 9643 AN: 251256 AF XY: 0.0317

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 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

African (AFR) AF: 0.256 AC: 8574 AN: 33440

American (AMR) AF: 0.0575 AC: 2571 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 369 AN: 26134

East Asian (EAS) AF: 0.117 AC: 4626 AN: 39686

South Asian (SAS) AF: 0.00558 AC: 481 AN: 86238

European-Finnish (FIN) AF: 0.0523 AC: 2792 AN: 53406

Middle Eastern (MID) AF: 0.0288 AC: 166 AN: 5764

European-Non Finnish (NFE) AF: 0.00229 AC: 2545 AN: 1111456

Other (OTH) AF: 0.0301 AC: 1814 AN: 60358

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

African (AFR) AF: 0.243 AC: 10096 AN: 41468

American (AMR) AF: 0.0640 AC: 979 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3468

East Asian (EAS) AF: 0.0855 AC: 442 AN: 5172

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.0545 AC: 578 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00423 AC: 288 AN: 68018

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0243 Hom.: 516

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
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4752; hg19: chr4-72622566; COSMIC: COSV56737625; COSMIC: COSV56737625;