4-56298287-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001393381.1(CRACD):c.58A>G(p.Ser20Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRACD NM_001393381.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20622599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRACD	NM_001393381.1	c.58A>G	p.Ser20Gly	missense_variant	4/11	ENST00000682029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRACD	ENST00000682029.1	c.58A>G	p.Ser20Gly	missense_variant	4/11		NM_001393381.1	A2
	ENST00000651073.1	n.968+619T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

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

Jul 13, 2022

The c.58A>G (p.S20G) alteration is located in exon 4 (coding exon 1) of the KIAA1211 gene. This alteration results from a A to G substitution at nucleotide position 58, causing the serine (S) at amino acid position 20 to be replaced by a glycine (G). 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	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.066	T;.;.;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.60	T;T;T;.;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.55	T
Sift4G	Pathogenic	0.0	D;.;.;D;D;.
Polyphen		0.99	.;.;.;D;D;.
Vest4		0.37, 0.33
MutPred		0.15		Gain of sheet (P = 0.0266);.;Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.36
MPC		0.88
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.065

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: rs1458397805; hg19: chr4-57164453;