5-150222717-T-C

Position:

• chr5-150222717-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015981.4(CAMK2A):​c.1467-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,612,872 control chromosomes in the GnomAD database, including 99,248 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 0.35 (9298 hom., cov: 32)
  • Exomes 𝑓: 0.35 (89950 hom.)
• Consequence: CAMK2A NM_015981.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008002
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.784

Genes affected

CAMK2A (HGNC:1460): (calcium/calmodulin dependent protein kinase II alpha) The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2018]

SLC6A7 (HGNC:11054): (solute carrier family 6 member 7) This gene is a member of the gamma-aminobutyric acid (GABA) neurotransmitter gene family and encodes a high-affinity mammalian brain L-proline transporter protein. This transporter protein differs from other sodium-dependent plasma membrane carriers by its pharmacological specificity, kinetic properties, and ionic requirements. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 5-150222717-T-C is Benign according to our data. Variant chr5-150222717-T-C is described in ClinVar as [Benign]. Clinvar id is 1192687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK2A	NM_015981.4	c.1467-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000671881.1	NP_057065.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK2A	ENST00000671881.1	c.1467-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_015981.4	ENSP00000500386	P3

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52840 AN: 151856 Hom.: 9297 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.348

GnomAD3 exomes AF: 0.345 AC: 85615 AN: 247872 Hom.: 15498 AF XY: 0.341 AC XY: 45879 AN XY: 134676

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.316

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.347 AC: 507387 AN: 1460898 Hom.: 89950 Cov.: 37 AF XY: 0.346 AC XY: 251323 AN XY: 726802

Gnomad4 AFR exome AF: 0.355

Gnomad4 AMR exome AF: 0.463

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.348 AC: 52860 AN: 151974 Hom.: 9298 Cov.: 32 AF XY: 0.345 AC XY: 25627 AN XY: 74280

Gnomad4 AFR AF: 0.361

Gnomad4 AMR AF: 0.392

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.357

Gnomad4 OTH AF: 0.343

Alfa AF: 0.322 Hom.: 3855

Bravo AF: 0.354

Asia WGS AF: 0.221 AC: 772 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.347

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 63 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Intellectual disability, autosomal dominant 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.8
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs55976097; hg19: chr5-149602280; COSMIC: COSV62245557;