Genetic Variant GC:p.Asp432Glu (chr4-71752617-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000583.4(GC):c.1296T>A(p.Asp432Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

GC
NM_000583.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.89

Publications

713 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061386228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GC	NM_000583.4 link	c.1296T>A	p.Asp432Glu	missense_variant	Exon 11 of 13	ENST00000273951.13	NP_000574.2
GC	NM_001204307.1 link	c.1353T>A	p.Asp451Glu	missense_variant	Exon 12 of 14		NP_001191236.1
GC	NM_001204306.1 link	c.1296T>A	p.Asp432Glu	missense_variant	Exon 12 of 14		NP_001191235.1
GC	NM_001440458.1 link	c.1262+1794T>A		intron_variant	Intron 10 of 11		NP_001427387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GC	ENST00000273951.13 link	c.1296T>A	p.Asp432Glu	missense_variant	Exon 11 of 13	1	NM_000583.4	ENSP00000273951.8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251206

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461078

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111370

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0010

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.073

T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.42

T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;.

PhyloP100

-3.9

PrimateAI

Benign

0.31

PROVEAN

Benign

0.76

N;N;N

REVEL

Benign

0.035

Sift

Benign

0.36

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.040

MutPred

0.39

Gain of glycosylation at T434 (P = 0.0279);.;Gain of glycosylation at T434 (P = 0.0279);

MVP

0.048

MPC

0.048

ClinPred

0.15

GERP RS

-10

Varity_R

0.17

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over