1-40067670-G-A

Variant names:

• chr1-40067670-G-A
• rs575446557
• NM_006367.4:c.761G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006367.4(CAP1):​c.761G>A​(p.Arg254His) variant causes a missense change. The variant allele was found at a frequency of 0.0000244 in 1,595,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R254C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CAP1 NM_006367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12
• Publications: 0 publications found

Genes affected

CAP1 (HGNC:20040): (cyclase associated actin cytoskeleton regulatory protein 1) The protein encoded by this gene is related to the S. cerevisiae CAP protein, which is involved in the cyclic AMP pathway. The human protein is able to interact with other molecules of the same protein, as well as with CAP2 and actin. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.16294593).
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006367.4. 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
	CAP1	NM_006367.4	MANE Select	c.761G>A	p.Arg254His	missense	Exon 8 of 13	NP_006358.2	Q01518-1
	CAP1	NM_001105530.2		c.761G>A	p.Arg254His	missense	Exon 8 of 13	NP_001099000.2	Q01518-1
	CAP1	NM_001350475.2		c.761G>A	p.Arg254His	missense	Exon 9 of 14	NP_001337404.2	Q01518-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAP1	ENST00000372805.8	TSL:1 MANE Select	c.761G>A	p.Arg254His	missense	Exon 8 of 13	ENSP00000361891.3	Q01518-1
	CAP1	ENST00000372792.7	TSL:1	c.761G>A	p.Arg254His	missense	Exon 8 of 13	ENSP00000361878.2	Q01518-1
	CAP1	ENST00000372797.7	TSL:1	c.761G>A	p.Arg254His	missense	Exon 8 of 13	ENSP00000361883.3	Q01518-1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150598 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000421

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000513 AC: 12 AN: 233766 AF XY: 0.0000705

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.000187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000235 AC: 34 AN: 1445172 Hom.: 0 Cov.: 29 AF XY: 0.0000334 AC XY: 24 AN XY: 719356

African (AFR) AF: 0.00 AC: 0 AN: 32234

American (AMR) AF: 0.00 AC: 0 AN: 41744

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25500

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38318

South Asian (SAS) AF: 0.000212 AC: 18 AN: 85048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1103748

Other (OTH) AF: 0.0000838 AC: 5 AN: 59646

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150710 Hom.: 0 Cov.: 30 AF XY: 0.0000544 AC XY: 4 AN XY: 73528

African (AFR) AF: 0.00 AC: 0 AN: 40936

American (AMR) AF: 0.0000661 AC: 1 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5084

South Asian (SAS) AF: 0.000422 AC: 2 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67758

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.076
Sift	Benign	0.073	T
Sift4G	Benign	0.18	T
Polyphen		0.10	B
Vest4		0.41
MutPred		0.48		Loss of phosphorylation at S256 (P = 0.0715)
MVP		0.58
MPC		0.46
ClinPred		0.17	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.44
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs575446557; hg19: chr1-40533342;