chr1-40064549-T-C

Variant names:

• chr1-40064549-T-C
• rs750834838
• NM_006367.4:c.514T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006367.4(CAP1):​c.514T>C​(p.Tyr172His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAP1 NM_006367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAP1	NM_006367.4	c.514T>C	p.Tyr172His	missense_variant	Exon 6 of 13	ENST00000372805.8	NP_006358.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAP1	ENST00000372805.8	c.514T>C	p.Tyr172His	missense_variant	Exon 6 of 13	1	NM_006367.4	ENSP00000361891.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249536 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135372

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459300 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726148

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514T>C (p.Y172H) alteration is located in exon 6 (coding exon 5) of the CAP1 gene. This alteration results from a T to C substitution at nucleotide position 514, causing the tyrosine (Y) at amino acid position 172 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	0.59
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T;T;T;T;T;.;.;T;.;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;D;D;D;D;.;.;D;D;D;D;T;D
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.;M;.;.;M;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.048	D;T;D;D;D;D;D;T;T;D;D;D;D;D
Sift4G	Benign	0.097	T;T;D;D;D;D;T;T;T;T;D;D;D;D
Polyphen		0.23	B;.;.;.;.;.;B;.;.;B;.;.;.;.
Vest4		0.68
MutPred		0.73		Gain of disorder (P = 0.0205);.;Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);.;.;Gain of disorder (P = 0.0205);.;Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);
MVP		0.50
MPC		0.59
ClinPred		0.92	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750834838; hg19: chr1-40530221;