chr7-44243526-G-A

Variant names:

• chr7-44243526-G-A
• rs1554389088
• NM_001220.5:c.416C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001220.5(CAMK2B):​c.416C>T​(p.Pro139Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P139P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAMK2B NM_001220.5 missense, splice_region
• Scores: Splicing: ADA: 0.8697
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.91
• Publications: 1 publications found

Genes affected

CAMK2B (HGNC:1461): (calcium/calmodulin dependent protein kinase II beta) The product of this gene belongs to the serine/threonine protein kinase family and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. In mammalian cells, the enzyme is composed of four different chains: alpha, beta, gamma, and delta. The product of this gene is a beta chain. It is possible that distinct isoforms of this chain have different cellular localizations and interact differently with calmodulin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

CAMK2B Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 40

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• intellectual disability, autosomal dominant 54

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 7-44243526-G-A is Pathogenic according to our data. Variant chr7-44243526-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 430922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001220.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2B	NM_001220.5	MANE Select	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 24	NP_001211.3
	CAMK2B	NM_001293170.2		c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 21	NP_001280099.1
	CAMK2B	NM_172078.3		c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 21	NP_742075.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMK2B	ENST00000395749.7	TSL:1 MANE Select	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 24	ENSP00000379098.2
	CAMK2B	ENST00000440254.6	TSL:1	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 21	ENSP00000397937.2
	CAMK2B	ENST00000395747.6	TSL:1	c.416C>T	p.Pro139Leu	missense splice_region	Exon 7 of 19	ENSP00000379096.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461274 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111704

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Intellectual disability, autosomal dominant 54 (9)
3	-	-	not provided (3)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Apnea;C0013421:Dystonic disorder;C0020578:Hyperventilation;C0085631:Agitation;C0557874:Global developmental delay;C4551563:Microcephaly (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.86		Gain of stability (P = 0.05)
MVP		0.62
MPC		2.8
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.83
gMVP		0.99
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Pathogenic	0.80
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

Other links and lift over

dbSNP: rs1554389088; hg19: chr7-44283125;