6-20546397-T-C

Position:

• chr6-20546397-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017774.3(CDKAL1):​c.47T>C​(p.Ile16Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CDKAL1 NM_017774.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKAL1	NM_017774.3	c.47T>C	p.Ile16Thr	missense_variant	3/16	ENST00000274695.8	NP_060244.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKAL1	ENST00000274695.8	c.47T>C	p.Ile16Thr	missense_variant	3/16	1	NM_017774.3	ENSP00000274695.4
CDKAL1	ENST00000613575.4	c.47T>C	p.Ile16Thr	missense_variant	4/6	1		ENSP00000481755.1
CDKAL1	ENST00000378610.1	c.47T>C	p.Ile16Thr	missense_variant	1/14	2		ENSP00000367873.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461708 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.47T>C (p.I16T) alteration is located in exon 3 (coding exon 1) of the CDKAL1 gene. This alteration results from a T to C substitution at nucleotide position 47, causing the isoleucine (I) at amino acid position 16 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	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;.;D
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.56	P;P;P
Vest4		0.59
MutPred		0.28		Gain of phosphorylation at I16 (P = 0.0295);Gain of phosphorylation at I16 (P = 0.0295);Gain of phosphorylation at I16 (P = 0.0295);
MVP		0.28
MPC		0.68
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.37
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-20546628;