Genetic Variant NM_021960.5:c.688+24A>G (chr1-150578819-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_021960.5(MCL1):c.688+24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,595,308 control chromosomes in the GnomAD database, including 1,415 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 0.030 ( 91 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1324 hom. )

Consequence

MCL1
NM_021960.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.822

Publications

6 publications found

Variant links:

Genes affected

MCL1 (HGNC:6943): (MCL1 apoptosis regulator, BCL2 family member) This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010]

MCL1 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 (BayesDel_noAF=-0.79).

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MCL1	NM_021960.5 link	c.688+24A>G	intron_variant	Intron 1 of 2	ENST00000369026.3	NP_068779.1	Q07820-1
MCL1	NM_182763.3 link	c.688+24A>G	intron_variant	Intron 1 of 1		NP_877495.1	Q07820-2
MCL1	NM_001197320.2 link	c.229+24A>G	intron_variant	Intron 2 of 3		NP_001184249.1	Q07820C8YZ26A0A087WT64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCL1	ENST00000369026.3 link	c.688+24A>G		intron_variant	Intron 1 of 2	1	NM_021960.5	ENSP00000358022.2		Q07820-1

Frequencies

GnomAD3 genomes

AF:

0.0299

AC:

4553

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0280

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0484

Gnomad FIN

AF:

0.0401

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0394

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0375

AC:

8967

AN:

239054

AF XY:

0.0409

show subpopulations

Gnomad AFR exome

AF:

0.00556

Gnomad AMR exome

AF:

0.0215

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.000166

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0398

Gnomad OTH exome

AF:

0.0464

GnomAD4 exome

AF:

0.0391

AC:

56409

AN:

1443108

Hom.:

1324

Cov.:

AF XY:

0.0402

AC XY:

28756

AN XY:

715922

show subpopulations

African (AFR)

AF:

0.00707

AC:

233

AN:

32936

American (AMR)

AF:

0.0223

AC:

953

AN:

42730

Ashkenazi Jewish (ASJ)

AF:

0.0952

AC:

2368

AN:

24886

East Asian (EAS)

AF:

0.000127

AC:

AN:

39484

South Asian (SAS)

AF:

0.0631

AC:

5358

AN:

84878

European-Finnish (FIN)

AF:

0.0427

AC:

2246

AN:

52552

Middle Eastern (MID)

AF:

0.104

AC:

587

AN:

5662

European-Non Finnish (NFE)

AF:

0.0384

AC:

42220

AN:

1100506

Other (OTH)

AF:

0.0410

AC:

2439

AN:

59474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3099

6197

9296

12394

15493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1652

3304

4956

6608

8260

<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:

0.0299

AC:

4550

AN:

152200

Hom.:

Cov.:

AF XY:

0.0305

AC XY:

2269

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00725

AC:

301

AN:

41544

American (AMR)

AF:

0.0280

AC:

428

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

361

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5174

South Asian (SAS)

AF:

0.0480

AC:

231

AN:

4814

European-Finnish (FIN)

AF:

0.0401

AC:

426

AN:

10612

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0394

AC:

2679

AN:

67984

Other (OTH)

AF:

0.0360

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

222

444

667

889

1111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0378

Hom.:

Bravo

AF:

0.0276

Asia WGS

AF:

0.0210

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.52

(source)

DANN

Benign

0.64

PhyloP100

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over