Genetic Variant NM_021960.5:c.732A>G (chr1-150578448-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021960.5(MCL1):c.732A>G(p.Lys244Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,144 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 102 hom. )

Consequence

MCL1
NM_021960.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0300

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 1-150578448-T-C is Benign according to our data. Variant chr1-150578448-T-C is described in ClinVar as Benign. ClinVar VariationId is 770854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0107 (15571/1461866) while in subpopulation MID AF = 0.0258 (149/5768). AF 95% confidence interval is 0.0225. There are 102 homozygotes in GnomAdExome4. There are 7822 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1234 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021960.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCL1	NM_021960.5	MANE Select	c.732A>G	p.Lys244Lys	synonymous	Exon 2 of 3	NP_068779.1	Q07820-1
MCL1	NM_001197320.2		c.273A>G	p.Lys91Lys	synonymous	Exon 3 of 4	NP_001184249.1	A0A087WT64
MCL1	NM_182763.3		c.688+395A>G		intron	N/A	NP_877495.1	Q07820-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCL1	ENST00000369026.3	TSL:1 MANE Select	c.732A>G	p.Lys244Lys	synonymous	Exon 2 of 3	ENSP00000358022.2	Q07820-1
MCL1	ENST00000620947.4	TSL:1	c.273A>G	p.Lys91Lys	synonymous	Exon 3 of 4	ENSP00000477624.1	A0A087WT64
MCL1	ENST00000307940.3	TSL:1	c.688+395A>G		intron	N/A	ENSP00000309973.3	Q07820-2

Frequencies

GnomAD3 genomes

AF:

0.00810

AC:

1233

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00900

AC:

2264

AN:

251462

AF XY:

0.00943

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.0402

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00309

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.0107

AC:

15571

AN:

1461866

Hom.:

102

Cov.:

AF XY:

0.0108

AC XY:

7822

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33480

American (AMR)

AF:

0.00816

AC:

365

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

1115

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00772

AC:

666

AN:

86258

European-Finnish (FIN)

AF:

0.00268

AC:

143

AN:

53414

Middle Eastern (MID)

AF:

0.0258

AC:

149

AN:

5768

European-Non Finnish (NFE)

AF:

0.0111

AC:

12324

AN:

1111992

Other (OTH)

AF:

0.0120

AC:

727

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

861

1722

2582

3443

4304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.00810

AC:

1234

AN:

152278

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

587

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41552

American (AMR)

AF:

0.0107

AC:

163

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0438

AC:

152

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00745

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

740

AN:

68020

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0111

Hom.:

Bravo

AF:

0.00867

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0114

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.1

(source)

DANN

Benign

0.81

PhyloP100

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over