Genetic Variant NM_002061.4:c.720C>T (chr1-93889095-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_002061.4(GCLM):c.720C>T(p.His240His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,602,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

GCLM
NM_002061.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.94

Publications

2 publications found

Variant links:

Genes affected

GCLM (HGNC:4312): (glutamate-cysteine ligase modifier subunit) Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase, is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

GCLM links:

ENSG00000310419 (HGNC:):

ENSG00000310419 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP7

Synonymous conserved (PhyloP=-3.94 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002061.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLM	NM_002061.4	MANE Select	c.720C>T	p.His240His	synonymous	Exon 7 of 7	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.654C>T	p.His218His	synonymous	Exon 6 of 6	NP_001295182.1	P48507-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCLM	ENST00000370238.8	TSL:1 MANE Select	c.720C>T	p.His240His	synonymous	Exon 7 of 7	ENSP00000359258.3	P48507-1
GCLM	ENST00000615724.1	TSL:1	c.654C>T	p.His218His	synonymous	Exon 6 of 6	ENSP00000484507.1	P48507-2
GCLM	ENST00000871361.1		c.774C>T	p.His258His	synonymous	Exon 8 of 8	ENSP00000541420.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

241532

AF XY:

0.0000229

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:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000759

AC:

AN:

1449900

Hom.:

Cov.:

AF XY:

0.00000971

AC XY:

AN XY:

721104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32840

American (AMR)

AF:

0.00

AC:

AN:

42772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

38818

South Asian (SAS)

AF:

0.00

AC:

AN:

84450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000904

AC:

AN:

1106142

Other (OTH)

AF:

0.0000167

AC:

AN:

59914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

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

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.075

(source)

DANN

Benign

0.87

PhyloP100

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over