chr6-21065218-C-T

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

2
10
6

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]

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
CDKAL1NM_017774.3 linkc.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
CDKAL1ENST00000274695.8 linkc.1226C>T p.Pro409Leu missense_variant Exon 12 of 16 1 NM_017774.3 ENSP00000274695.4 Q5VV42-1
CDKAL1ENST00000378610.1 linkc.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.:
32
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.:
30
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
0
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
0
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.:
32
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:
21
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
0
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
0
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
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.70
D;D
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.90
D;.
MetaRNN
Benign
0.0022
T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Pathogenic
3.8
H;H
PhyloP100
5.7
PrimateAI
Uncertain
0.66
T
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
T
GERP RS
5.5
Varity_R
0.60
gMVP
0.85
Mutation Taster
=86/14
polymorphism (auto)

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

Other links and lift over

dbSNP: rs77152992; hg19: chr6-21065449; COSMIC: COSV51183600; API