4-56307698-A-G

Variant names:

• chr4-56307698-A-G
• rs767428217
• NM_001393381.1:c.284A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001393381.1(CRACD):​c.284A>G​(p.Lys95Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K95M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRACD NM_001393381.1 missense, splice_region
• Scores: Splicing: ADA: 0.9733
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.48
• Publications: 1 publications found

Genes affected

CRACD (HGNC:29219): (capping protein inhibiting regulator of actin dynamics) Involved in negative regulation of barbed-end actin filament capping. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18345228).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393381.1. 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
	CRACD	NM_001393381.1	MANE Select	c.284A>G	p.Lys95Arg	missense splice_region	Exon 5 of 11	NP_001380310.1	Q6ZU35
	CRACD	NM_001393382.1		c.284A>G	p.Lys95Arg	missense splice_region	Exon 4 of 10	NP_001380311.1	Q6ZU35
	CRACD	NM_020722.2		c.284A>G	p.Lys95Arg	missense splice_region	Exon 5 of 11	NP_065773.1	Q6ZU35

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRACD	ENST00000682029.1	MANE Select	c.284A>G	p.Lys95Arg	missense splice_region	Exon 5 of 11	ENSP00000507165.1	Q6ZU35
	CRACD	ENST00000541073.5	TSL:1	c.263A>G	p.Lys88Arg	missense splice_region	Exon 4 of 10	ENSP00000444006.1	F5H1N7
	CRACD	ENST00000646253.2		c.539A>G	p.Lys180Arg	missense splice_region	Exon 6 of 12	ENSP00000495373.2	A0A2R8Y6P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249340 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.073
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.034	D
Polyphen		0.98	D
Vest4		0.23
MutPred		0.17		Loss of ubiquitination at K95 (P = 0.0023)
MVP		0.30
MPC		0.85
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.096
gMVP		0.11
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.70
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: rs767428217; hg19: chr4-57173864;