Genetic Variant CAMKV:p.Glu440Asp (chr3-49859504-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_024046.5(CAMKV):c.1320G>T(p.Glu440Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CAMKV
NM_024046.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.413

Variant links:

Genes affected

CAMKV (HGNC:28788): (CaM kinase like vesicle associated) Predicted to enable calmodulin binding activity and calmodulin-dependent protein kinase activity. Predicted to be involved in peptidyl-serine phosphorylation. Predicted to be located in cytoplasmic vesicle membrane and plasma membrane. Predicted to be active in glutamatergic synapse and postsynapse. [provided by Alliance of Genome Resources, Apr 2022]

CAMKV links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07790527).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAMKV	NM_024046.5 link	c.1320G>T	p.Glu440Asp	missense_variant	Exon 11 of 11	ENST00000477224.6	NP_076951.2	Q8NCB2-1A0A140VKD5
CAMKV	NM_001320147.2 link	c.1227G>T	p.Glu409Asp	missense_variant	Exon 12 of 12		NP_001307076.1	Q8NCB2-3A0A024R331

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMKV	ENST00000477224.6 link	c.1320G>T	p.Glu440Asp	missense_variant	Exon 11 of 11	1	NM_024046.5	ENSP00000419195.1		Q8NCB2-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000956

AC:

AN:

250984

AF XY:

0.0000811

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000228

AC:

334

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000290

AC:

322

AN:

1112004

Other (OTH)

AF:

0.000132

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000118

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41450

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000173

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1320G>T (p.E440D) alteration is located in exon 11 (coding exon 10) of the CAMKV gene. This alteration results from a G to T substitution at nucleotide position 1320, causing the glutamic acid (E) at amino acid position 440 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

.;.;T;.;T;T

Eigen

Benign

0.072

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.72

.;T;T;T;T;T

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.078

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

.;.;N;.;.;.

PhyloP100

0.41

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.48

N;N;N;.;N;N

REVEL

Benign

0.089

Sift

Uncertain

0.021

D;D;D;.;D;D

Sift4G

Benign

0.42

T;T;T;T;.;T

Polyphen

0.75

P;P;P;P;D;P

Vest4

0.062

MutPred

0.10

.;.;Loss of glycosylation at T445 (P = 0.0621);.;.;.;

MVP

0.49

MPC

0.70

ClinPred

0.093

GERP RS

4.5

Varity_R

0.084

gMVP

0.054

Mutation Taster

=88/12

polymorphism

(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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3-49859504-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over