Genetic Variant CAMK2A:p.Asp470Asp (chr5-150223045-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015981.4(CAMK2A):c.1410T>C(p.Asp470Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 1,614,194 control chromosomes in the GnomAD database, including 680,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 66995 hom., cov: 36)

Exomes 𝑓: 0.92 ( 613745 hom. )

Consequence

CAMK2A
NM_015981.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.439

Publications

25 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability, autosomal recessive 63
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CAMK2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 5-150223045-A-G is Benign according to our data. Variant chr5-150223045-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.439 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

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.1410T>C	p.Asp470Asp	synonymous	Exon 18 of 19	NP_057065.2
CAMK2A	NM_001363989.1		c.1410T>C	p.Asp470Asp	synonymous	Exon 19 of 20	NP_001350918.1	Q9UQM7-2
CAMK2A	NM_001363990.1		c.1377T>C	p.Asp459Asp	synonymous	Exon 18 of 19	NP_001350919.1	Q7LDD5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAMK2A	ENST00000671881.1	MANE Select	c.1410T>C	p.Asp470Asp	synonymous	Exon 18 of 19	ENSP00000500386.1	Q9UQM7-2
CAMK2A	ENST00000348628.11	TSL:1	c.1377T>C	p.Asp459Asp	synonymous	Exon 17 of 18	ENSP00000261793.8	Q9UQM7-1
CAMK2A	ENST00000398376.8	TSL:1	c.1206T>C	p.Asp402Asp	synonymous	Exon 15 of 16	ENSP00000381412.4	A0A5K1VW76

Frequencies

GnomAD3 genomes

AF:

0.937

AC:

142647

AN:

152226

Hom.:

66935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.985

Gnomad AMI

AF:

0.861

Gnomad AMR

AF:

0.954

Gnomad ASJ

AF:

0.917

Gnomad EAS

AF:

0.834

Gnomad SAS

AF:

0.836

Gnomad FIN

AF:

0.935

Gnomad MID

AF:

0.946

Gnomad NFE

AF:

0.921

Gnomad OTH

AF:

0.950

GnomAD2 exomes

AF:

0.918

AC:

228671

AN:

249086

AF XY:

0.912

show subpopulations

Gnomad AFR exome

AF:

0.987

Gnomad AMR exome

AF:

0.967

Gnomad ASJ exome

AF:

0.914

Gnomad EAS exome

AF:

0.831

Gnomad FIN exome

AF:

0.931

Gnomad NFE exome

AF:

0.925

Gnomad OTH exome

AF:

0.916

GnomAD4 exome

AF:

0.916

AC:

1338932

AN:

1461850

Hom.:

613745

Cov.:

AF XY:

0.914

AC XY:

664456

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.987

AC:

33059

AN:

33480

American (AMR)

AF:

0.967

AC:

43232

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

23971

AN:

26136

East Asian (EAS)

AF:

0.848

AC:

33656

AN:

39700

South Asian (SAS)

AF:

0.849

AC:

73209

AN:

86252

European-Finnish (FIN)

AF:

0.931

AC:

49687

AN:

53388

Middle Eastern (MID)

AF:

0.937

AC:

5407

AN:

5768

European-Non Finnish (NFE)

AF:

0.919

AC:

1021524

AN:

1112006

Other (OTH)

AF:

0.914

AC:

55187

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

7012

14024

21035

28047

35059

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21508

43016

64524

86032

107540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.937

AC:

142767

AN:

152344

Hom.:

66995

Cov.:

AF XY:

0.936

AC XY:

69713

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.985

AC:

40969

AN:

41588

American (AMR)

AF:

0.954

AC:

14596

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.917

AC:

3182

AN:

3470

East Asian (EAS)

AF:

0.834

AC:

4316

AN:

5176

South Asian (SAS)

AF:

0.836

AC:

4041

AN:

4834

European-Finnish (FIN)

AF:

0.935

AC:

9926

AN:

10620

Middle Eastern (MID)

AF:

0.946

AC:

278

AN:

294

European-Non Finnish (NFE)

AF:

0.921

AC:

62668

AN:

68030

Other (OTH)

AF:

0.948

AC:

2006

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

488

975

1463

1950

2438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.928

Hom.:

134283

Bravo

AF:

0.942

Asia WGS

AF:

0.834

AC:

2901

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, autosomal dominant 53 (1)

Intellectual disability, autosomal recessive 63 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.10

(source)

DANN

Benign

0.59

PhyloP100

-0.44

Mutation Taster

=83/17

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over