chr9-135815899-C-T

Variant names:

• chr9-135815899-C-T
• rs1250332952
• NM_015447.4:c.4378G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015447.4(CAMSAP1):​c.4378G>A​(p.Glu1460Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,424 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CAMSAP1 NM_015447.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61
• Publications: 1 publications found

Genes affected

CAMSAP1 (HGNC:19946): (calmodulin regulated spectrin associated protein 1) Enables microtubule minus-end binding activity and spectrin binding activity. Involved in several processes, including neuron projection development; regulation of cell morphogenesis; and regulation of microtubule polymerization. Located in microtubule. Colocalizes with microtubule minus-end. [provided by Alliance of Genome Resources, Apr 2022]

CAMSAP1 Gene-Disease associations (from GenCC):

• cortical dysplasia, complex, with other brain malformations 12

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015447.4. 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
	CAMSAP1	NM_015447.4	MANE Select	c.4378G>A	p.Glu1460Lys	missense	Exon 15 of 17	NP_056262.3	Q5T5Y3-1
	CAMSAP1	NM_001437279.1		c.4411G>A	p.Glu1471Lys	missense	Exon 16 of 18	NP_001424208.1
	CAMSAP1	NM_001437280.1		c.3946G>A	p.Glu1316Lys	missense	Exon 14 of 16	NP_001424209.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMSAP1	ENST00000389532.9	TSL:5 MANE Select	c.4378G>A	p.Glu1460Lys	missense	Exon 15 of 17	ENSP00000374183.4	Q5T5Y3-1
	CAMSAP1	ENST00000312405.10	TSL:1	c.3544G>A	p.Glu1182Lys	missense	Exon 13 of 15	ENSP00000312463.6	Q5T5Y3-2
	CAMSAP1	ENST00000409386.3	TSL:5	c.4411G>A	p.Glu1471Lys	missense	Exon 16 of 18	ENSP00000386420.3	Q5T5Y3-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250374 AF XY: 0.00000738

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461144 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726878

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74400

African (AFR) AF: 0.00 AC: 0 AN: 41484

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.0055	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.28		Gain of methylation at E1460 (P = 0.0081)
MVP		0.32
MPC		1.8
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.65
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1250332952; hg19: chr9-138707745; COSMIC: COSV56723112; COSMIC: COSV56723112;