12-121249958-C-T

Variant names:

• chr12-121249958-C-T
• rs76155360
• NM_001270485.2:c.1235+3G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001270485.2(CAMKK2):​c.1235+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,613,992 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (204 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (169 hom.)
• Consequence: CAMKK2 NM_001270485.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003395
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.326

Genes affected

CAMKK2 (HGNC:1470): (calcium/calmodulin dependent protein kinase kinase 2) The product of this gene belongs to the Serine/Threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. The major isoform of this gene plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4. Protein products of this gene also phosphorylate AMP-activated protein kinase (AMPK). This gene has its strongest expression in the brain and influences signalling cascades involved with learning and memory, neuronal differentiation and migration, neurite outgrowth, and synapse formation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. The identified isoforms differ in their ability to undergo autophosphorylation and to phosphorylate downstream kinases. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 12-121249958-C-T is Benign according to our data. Variant chr12-121249958-C-T is described in ClinVar as [Benign]. Clinvar id is 781091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMKK2	NM_001270485.2	c.1235+3G>A		splice_region_variant, intron_variant	Intron 12 of 16	ENST00000404169.8	NP_001257414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMKK2	ENST00000404169.8	c.1235+3G>A		splice_region_variant, intron_variant	Intron 12 of 16	1	NM_001270485.2	ENSP00000384600.3

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4134 AN: 152102 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00764 AC: 1920 AN: 251372 AF XY: 0.00563

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00298 AC: 4356 AN: 1461772 Hom.: 169 Cov.: 32 AF XY: 0.00259 AC XY: 1885 AN XY: 727190

Gnomad4 AFR exome AF: 0.0951 AC: 3182 AN: 33462

Gnomad4 AMR exome AF: 0.00615 AC: 275 AN: 44724

Gnomad4 ASJ exome AF: 0.000803 AC: 21 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.000151 AC: 13 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.000398 AC: 442 AN: 1111914

Gnomad4 Remaining exome AF: 0.00639 AC: 386 AN: 60392

GnomAD4 genome AF: 0.0273 AC: 4150 AN: 152220 Hom.: 204 Cov.: 32 AF XY: 0.0258 AC XY: 1922 AN XY: 74458

Gnomad4 AFR AF: 0.0947 AC: 0.0947333 AN: 0.0947333

Gnomad4 AMR AF: 0.00830 AC: 0.00830391 AN: 0.00830391

Gnomad4 ASJ AF: 0.00230 AC: 0.00230415 AN: 0.00230415

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000544 AC: 0.000544022 AN: 0.000544022

Gnomad4 OTH AF: 0.0189 AC: 0.0189394 AN: 0.0189394

Alfa AF: 0.0150 Hom.: 55

Bravo AF: 0.0314

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.86
Mutation Taster		=64/36	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.020
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

LitVar

Other links and lift over

dbSNP: rs76155360; hg19: chr12-121687761;