chr6-21065218-C-T

Variant names:

• chr6-21065218-C-T
• rs77152992
• NM_017774.3:c.1226C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.66
• Publications: 25 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017774.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKAL1	NM_017774.3	MANE Select	c.1226C>T	p.Pro409Leu	missense	Exon 12 of 16	NP_060244.2	Q5VV42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKAL1	ENST00000274695.8	TSL:1 MANE Select	c.1226C>T	p.Pro409Leu	missense	Exon 12 of 16	ENSP00000274695.4	Q5VV42-1
	CDKAL1	ENST00000946780.1		c.1334C>T	p.Pro445Leu	missense	Exon 13 of 17	ENSP00000616839.1
	CDKAL1	ENST00000378610.1	TSL:2	c.1226C>T	p.Pro409Leu	missense	Exon 10 of 14	ENSP00000367873.1	Q5VV42-1

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 8700 AN: 152078 Hom.: 292 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.0572 AC: 8701 AN: 152196 Hom.: 292 Cov.: 32 AF XY: 0.0597 AC XY: 4438 AN XY: 74398

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

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 v4.9

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
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
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.20	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

Other links and lift over

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