Genetic Variant GCA:p.Ser80Ala (chr2-162352383-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012198.5(GCA):c.238T>G(p.Ser80Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,582,658 control chromosomes in the GnomAD database, including 13,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.096 ( 922 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12415 hom. )

Consequence

GCA
NM_012198.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

Publications

37 publications found

Variant links:

Genes affected

GCA (HGNC:15990): (grancalcin) This gene encodes a calcium-binding protein that is abundant in neutrophils and macrophages. In the absence of divalent cation, this protein localizes to the cytosolic fraction; with magnesium alone, it partitions with the granule fraction; and in the presence of magnesium and calcium, it associates with both the granule and membrane fractions. Alternative splicing and use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Aug 2016]

GCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014909804).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCA	NM_012198.5 link	c.238T>G	p.Ser80Ala	missense_variant	Exon 3 of 8	ENST00000437150.7	NP_036330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCA	ENST00000437150.7 link	c.238T>G	p.Ser80Ala	missense_variant	Exon 3 of 8	1	NM_012198.5	ENSP00000394842.2

Frequencies

GnomAD3 genomes

AF:

0.0957

AC:

14551

AN:

152098

Hom.:

922

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0262

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0577

Gnomad FIN

AF:

0.0987

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.121

GnomAD2 exomes

AF:

0.106

AC:

26427

AN:

250464

AF XY:

0.109

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.0681

Gnomad ASJ exome

AF:

0.227

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.147

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.123

AC:

176333

AN:

1430442

Hom.:

12415

Cov.:

AF XY:

0.123

AC XY:

87544

AN XY:

713640

show subpopulations

African (AFR)

AF:

0.0248

AC:

819

AN:

33062

American (AMR)

AF:

0.0718

AC:

3199

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

5771

AN:

25882

East Asian (EAS)

AF:

0.000355

AC:

AN:

39474

South Asian (SAS)

AF:

0.0588

AC:

5031

AN:

85626

European-Finnish (FIN)

AF:

0.110

AC:

5864

AN:

53362

Middle Eastern (MID)

AF:

0.240

AC:

1361

AN:

5662

European-Non Finnish (NFE)

AF:

0.136

AC:

146814

AN:

1083498

Other (OTH)

AF:

0.126

AC:

7460

AN:

59306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

6157

12314

18471

24628

30785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5000

10000

15000

20000

25000

<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:

0.0956

AC:

14547

AN:

152216

Hom.:

922

Cov.:

AF XY:

0.0940

AC XY:

6994

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0261

AC:

1086

AN:

41570

American (AMR)

AF:

0.103

AC:

1575

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

756

AN:

3470

East Asian (EAS)

AF:

0.00154

AC:

AN:

5190

South Asian (SAS)

AF:

0.0579

AC:

279

AN:

4818

European-Finnish (FIN)

AF:

0.0987

AC:

1046

AN:

10598

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9384

AN:

67966

Other (OTH)

AF:

0.120

AC:

254

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

663

1325

1988

2650

3313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.129

Hom.:

5135

Bravo

AF:

0.0947

TwinsUK

AF:

0.142

AC:

525

ESP6500AA

AF:

0.0318

AC:

140

ESP6500EA

AF:

0.145

AC:

1247

ExAC

AF:

0.107

AC:

12963

Asia WGS

AF:

0.0320

AC:

113

AN:

3474

EpiCase

AF:

0.155

EpiControl

AF:

0.160

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;T;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.010

LIST_S2

Benign

0.53

T;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

.;.;L;.;.

PhyloP100

2.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N;N;N;N

Sift

Benign

0.32

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Vest4

0.0

ClinPred

0.010

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.44

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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