dbSNP rs1554122526: CAMK2A:p.Phe98Ser (chr5-150256811-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_015981.4(CAMK2A):c.293T>C(p.Phe98Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

CAMK2A
NM_015981.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 6.28

Publications

2 publications found

Variant links:

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]

CAMK2A Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal dominant 53
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability, autosomal recessive 63
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CAMK2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 5-150256811-A-G is Pathogenic according to our data. Variant chr5-150256811-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 430912.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015981.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAMK2A	NM_015981.4	MANE Select	c.293T>C	p.Phe98Ser	missense	Exon 5 of 19	NP_057065.2
CAMK2A	NM_001363989.1		c.293T>C	p.Phe98Ser	missense	Exon 6 of 20	NP_001350918.1	Q9UQM7-2
CAMK2A	NM_001363990.1		c.293T>C	p.Phe98Ser	missense	Exon 6 of 19	NP_001350919.1	Q7LDD5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAMK2A	ENST00000671881.1	MANE Select	c.293T>C	p.Phe98Ser	missense	Exon 5 of 19	ENSP00000500386.1	Q9UQM7-2
CAMK2A	ENST00000348628.11	TSL:1	c.293T>C	p.Phe98Ser	missense	Exon 5 of 18	ENSP00000261793.8	Q9UQM7-1
CAMK2A	ENST00000398376.8	TSL:1	c.293T>C	p.Phe98Ser	missense	Exon 5 of 16	ENSP00000381412.4	A0A5K1VW76

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

Intellectual disability, autosomal dominant 53 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.7

PhyloP100

6.3

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.80

MutPred

0.78

Gain of disorder (P = 0.0084)

MVP

0.94

MPC

4.3

ClinPred

1.0

GERP RS

4.3

Varity_R

0.94

gMVP

0.99

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over