chr3-9763155-A-G

Position:

• chr3-9763155-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003656.5(CAMK1):​c.274T>C​(p.Tyr92His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAMK1 NM_003656.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

Genes affected

CAMK1 (HGNC:1459): (calcium/calmodulin dependent protein kinase I) Calcium/calmodulin-dependent protein kinase I is expressed in many tissues and is a component of a calmodulin-dependent protein kinase cascade. Calcium/calmodulin directly activates calcium/calmodulin-dependent protein kinase I by binding to the enzyme and indirectly promotes the phosphorylation and synergistic activation of the enzyme by calcium/calmodulin-dependent protein kinase I kinase. [provided by RefSeq, Jul 2008]

OGG1 (HGNC:8125): (8-oxoguanine DNA glycosylase) This gene encodes the enzyme responsible for the excision of 8-oxoguanine, a mutagenic base byproduct which occurs as a result of exposure to reactive oxygen. The action of this enzyme includes lyase activity for chain cleavage. Alternative splicing of the C-terminal region of this gene classifies splice variants into two major groups, type 1 and type 2, depending on the last exon of the sequence. Type 1 alternative splice variants end with exon 7 and type 2 end with exon 8. All variants share the N-terminal region in common, which contains a mitochondrial targeting signal that is essential for mitochondrial localization. Many alternative splice variants for this gene have been described, but the full-length nature for every variant has not been determined. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAMK1	NM_003656.5	c.274T>C	p.Tyr92His	missense_variant	4/12	ENST00000256460.8	NP_003647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAMK1	ENST00000256460.8	c.274T>C	p.Tyr92His	missense_variant	4/12	1	NM_003656.5	ENSP00000256460.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.274T>C (p.Y92H) alteration is located in exon 4 (coding exon 3) of the CAMK1 gene. This alteration results from a T to C substitution at nucleotide position 274, causing the tyrosine (Y) at amino acid position 92 to be replaced by a histidine (H). 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.062	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.99	D;.
Vest4		0.94
MutPred		0.72		Gain of sheet (P = 0.0827);.;
MVP		0.82
MPC		0.89
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-9804839;