Genetic Variant NM_001358008.2:c.757G>A (chr5-178186543-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001358008.2(GMCL2):c.757G>A(p.Gly253Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,300,708 control chromosomes in the GnomAD database, including 8,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 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 0.14 ( 1778 hom., cov: 33)

Exomes 𝑓: 0.11 ( 7170 hom. )

Consequence

GMCL2
NM_001358008.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.333

Publications

14 publications found

Variant links:

Genes affected

GMCL2 (HGNC:19717): (germ cell-less 2, spermatogenesis associated) This locus shares a high degree of identity with the multi-exon germ cell-less gene on chromosome 2. Despite its single-exon nature, this chromosome 5 locus contains an open reading frame that could putatively encode a full-length germ cell-less related protein. [provided by RefSeq, Jul 2008]

GMCL2 links:

ENSG00000289726 (HGNC:):

ENSG00000289726 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0033006966).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMCL2	NM_001358008.2 link	c.757G>A	p.Gly253Ser	missense_variant	Exon 1 of 1	ENST00000463439.3	NP_001344937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMCL2	ENST00000463439.3 link	c.757G>A	p.Gly253Ser	missense_variant	Exon 1 of 1	6	NM_001358008.2	ENSP00000497178.1		Q8NEA9
ENSG00000289726	ENST00000697324.1 link	n.328+3552C>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20523

AN:

152038

Hom.:

1773

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0871

Gnomad ASJ

AF:

0.0585

Gnomad EAS

AF:

0.0179

Gnomad SAS

AF:

0.0646

Gnomad FIN

AF:

0.0969

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0954

AC:

23978

AN:

251360

AF XY:

0.0930

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.0651

Gnomad ASJ exome

AF:

0.0621

Gnomad EAS exome

AF:

0.00788

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.107

Gnomad OTH exome

AF:

0.0912

GnomAD4 exome

AF:

0.106

AC:

121308

AN:

1148552

Hom.:

7170

Cov.:

AF XY:

0.104

AC XY:

60692

AN XY:

586212

show subpopulations

African (AFR)

AF:

0.247

AC:

6837

AN:

27692

American (AMR)

AF:

0.0656

AC:

2910

AN:

44346

Ashkenazi Jewish (ASJ)

AF:

0.0624

AC:

1509

AN:

24198

East Asian (EAS)

AF:

0.0420

AC:

1608

AN:

38254

South Asian (SAS)

AF:

0.0715

AC:

5700

AN:

79740

European-Finnish (FIN)

AF:

0.105

AC:

5601

AN:

53306

Middle Eastern (MID)

AF:

0.0870

AC:

447

AN:

5140

European-Non Finnish (NFE)

AF:

0.111

AC:

91563

AN:

825904

Other (OTH)

AF:

0.103

AC:

5133

AN:

49972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

6055

12110

18164

24219

30274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.135

AC:

20548

AN:

152156

Hom.:

1778

Cov.:

AF XY:

0.132

AC XY:

9808

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.242

AC:

10022

AN:

41492

American (AMR)

AF:

0.0870

AC:

1329

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0585

AC:

203

AN:

3470

East Asian (EAS)

AF:

0.0179

AC:

AN:

5186

South Asian (SAS)

AF:

0.0636

AC:

307

AN:

4824

European-Finnish (FIN)

AF:

0.0969

AC:

1026

AN:

10588

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7286

AN:

68002

Other (OTH)

AF:

0.107

AC:

225

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

873

1746

2618

3491

4364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.114

Hom.:

2240

Bravo

AF:

0.137

TwinsUK

AF:

0.100

AC:

371

ALSPAC

AF:

0.110

AC:

423

ExAC

AF:

0.101

AC:

12302

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.2

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.0088

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0033

PhyloP100

0.33

Polyphen

0.0

GERP RS

-0.0076

Varity_R

0.043

gMVP

0.30

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001358008.2:c.757G>A

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