Genetic Variant NM_000583.4:c.897T>C (chr4-71756849-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.307

Publications

16 publications found

Variant links:

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]

GC links:

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ACMG classification

Classification was made for transcript

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 link	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 8 of 13	ENST00000273951.13	NP_000574.2	P02774-1
GC	NM_001204307.1 link	c.954T>C	p.Cys318Cys	synonymous_variant	Exon 9 of 14		NP_001191236.1	P02774-3
GC	NM_001204306.1 link	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 9 of 14		NP_001191235.1	P02774-1
GC	NM_001440458.1 link	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 link	c.897T>C	p.Cys299Cys	synonymous_variant	Exon 8 of 13	1	NM_000583.4	ENSP00000273951.8		P02774-1

Frequencies

GnomAD3 genomes

AF:

0.0830

AC:

12614

AN:

152054

Hom.:

1290

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0152

AC XY:

11021

AN XY:

726948

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1085

2171

3256

4342

5427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0830

AC:

12636

AN:

152172

Hom.:

1293

Cov.:

AF XY:

0.0838

AC XY:

6230

AN XY:

74386

show subpopulations

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:

AN:

3468

East Asian (EAS)

AF:

0.0855

AC:

442

AN:

5172

South Asian (SAS)

AF:

0.00456

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0545

AC:

578

AN:

10610

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00423

AC:

288

AN:

68018

Other (OTH)

AF:

0.0743

AC:

157

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

511

1022

1532

2043

2554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.60

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over