chr6-21000263-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017774.3(CDKAL1):​c.946G>A​(p.Ala316Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,648 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CDKAL1
NM_017774.3 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.38
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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.36412477).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKAL1NM_017774.3 linkuse as main transcriptc.946G>A p.Ala316Thr missense_variant 11/16 ENST00000274695.8 NP_060244.2 Q5VV42-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKAL1ENST00000274695.8 linkuse as main transcriptc.946G>A p.Ala316Thr missense_variant 11/161 NM_017774.3 ENSP00000274695.4 Q5VV42-1
CDKAL1ENST00000378610.1 linkuse as main transcriptc.946G>A p.Ala316Thr missense_variant 9/142 ENSP00000367873.1 Q5VV42-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152068
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461580
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
727090
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152068
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000674
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 10, 2024The c.946G>A (p.A316T) alteration is located in exon 11 (coding exon 9) of the CDKAL1 gene. This alteration results from a G to A substitution at nucleotide position 946, causing the alanine (A) at amino acid position 316 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;T
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.98
D;.
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
1.3
L;L
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.0
N;N
REVEL
Uncertain
0.37
Sift
Benign
0.057
T;T
Sift4G
Benign
0.061
T;T
Polyphen
0.77
P;P
Vest4
0.48
MVP
0.47
MPC
0.68
ClinPred
0.93
D
GERP RS
4.6
Varity_R
0.088
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1181710496; hg19: chr6-21000494; API