Genetic Variant CDKAL1:p.Pro409Leu (chr6-21065218-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_017774.3(CDKAL1):c.1226C>T(p.Pro409Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0518 in 1,604,816 control chromosomes in the GnomAD database, including 2,680 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 0.057 ( 292 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2388 hom. )

Consequence

CDKAL1
NM_017774.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.66

Publications

25 publications found

Variant links:

Genes affected

CDKAL1 (HGNC:21050): (CDK5 regulatory subunit associated protein 1 like 1) The protein encoded by this gene is a member of the methylthiotransferase family. The function of this gene is not known. Genome-wide association studies have linked single nucleotide polymorphisms in an intron of this gene with susceptibilty to type 2 diabetes. [provided by RefSeq, May 2010]

CDKAL1 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=0.0021731853).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKAL1	NM_017774.3 link	c.1226C>T	p.Pro409Leu	missense_variant	Exon 12 of 16	ENST00000274695.8	NP_060244.2	Q5VV42-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKAL1	ENST00000274695.8 link	c.1226C>T	p.Pro409Leu	missense_variant	Exon 12 of 16	1	NM_017774.3	ENSP00000274695.4		Q5VV42-1
CDKAL1	ENST00000378610.1 link	c.1226C>T	p.Pro409Leu	missense_variant	Exon 10 of 14	2		ENSP00000367873.1		Q5VV42-1

Frequencies

GnomAD3 genomes

AF:

0.0572

AC:

8700

AN:

152078

Hom.:

292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0659

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0901

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.0646

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0433

Gnomad OTH

AF:

0.0588

GnomAD2 exomes

AF:

0.0642

AC:

15661

AN:

244014

AF XY:

0.0661

show subpopulations

Gnomad AFR exome

AF:

0.0644

Gnomad AMR exome

AF:

0.0391

Gnomad ASJ exome

AF:

0.0956

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.0464

Gnomad OTH exome

AF:

0.0607

GnomAD4 exome

AF:

0.0512

AC:

74352

AN:

1452620

Hom.:

2388

Cov.:

AF XY:

0.0527

AC XY:

38046

AN XY:

721826

show subpopulations

African (AFR)

AF:

0.0691

AC:

2285

AN:

33066

American (AMR)

AF:

0.0401

AC:

1737

AN:

43366

Ashkenazi Jewish (ASJ)

AF:

0.0946

AC:

2462

AN:

26014

East Asian (EAS)

AF:

0.129

AC:

5067

AN:

39184

South Asian (SAS)

AF:

0.101

AC:

8399

AN:

82924

European-Finnish (FIN)

AF:

0.0560

AC:

2987

AN:

53360

Middle Eastern (MID)

AF:

0.0890

AC:

512

AN:

5752

European-Non Finnish (NFE)

AF:

0.0427

AC:

47390

AN:

1108818

Other (OTH)

AF:

0.0584

AC:

3513

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3104

6208

9312

12416

15520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1898

3796

5694

7592

9490

<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:

0.0572

AC:

8701

AN:

152196

Hom.:

292

Cov.:

AF XY:

0.0597

AC XY:

4438

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0659

AC:

2736

AN:

41518

American (AMR)

AF:

0.0406

AC:

621

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0901

AC:

313

AN:

3472

East Asian (EAS)

AF:

0.147

AC:

761

AN:

5162

South Asian (SAS)

AF:

0.101

AC:

486

AN:

4812

European-Finnish (FIN)

AF:

0.0646

AC:

685

AN:

10598

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0432

AC:

2941

AN:

68014

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

415

830

1245

1660

2075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0537

Hom.:

558

Bravo

AF:

0.0560

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.0604

AC:

266

ESP6500EA

AF:

0.0448

AC:

385

ExAC

AF:

0.0654

AC:

7947

Asia WGS

AF:

0.107

AC:

373

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;.

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.8

H;H

PhyloP100

5.7

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-9.0

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.20

B;B

Vest4

0.25

MPC

0.36

ClinPred

0.12

GERP RS

5.5

Varity_R

0.60

gMVP

0.85

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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