9-83748356-A-G

Position:

• chr9-83748356-A-G

Variant summary

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

The NM_025211.4(GKAP1):​c.857T>C​(p.Val286Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,426,190 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: GKAP1 NM_025211.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81

Genes affected

GKAP1 (HGNC:17496): (G kinase anchoring protein 1) This gene encodes a protein that is highly similar to the mouse cGMP-dependent protein kinase anchoring protein 42kDa. The mouse protein has been found to localize with the Golgi and recruit cGMP-dependent protein kinase I alpha to the Golgi in mouse testes. It is thought to play a role in germ cell development. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

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/exons	MANE	Protein	UniProt
GKAP1	NM_025211.4	c.857T>C	p.Val286Ala	missense_variant	10/13	ENST00000376371.7	NP_079487.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GKAP1	ENST00000376371.7	c.857T>C	p.Val286Ala	missense_variant	10/13	1	NM_025211.4	ENSP00000365550	P1
GKAP1	ENST00000376365.7	c.704T>C	p.Val235Ala	missense_variant	9/12	1		ENSP00000365544
GKAP1	ENST00000376362.1	n.800T>C		non_coding_transcript_exon_variant	1/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1426190 Hom.: 0 Cov.: 24 AF XY: 0.00000422 AC XY: 3 AN XY: 710234

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: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 30, 2021

The c.857T>C (p.V286A) alteration is located in exon 10 (coding exon 8) of the GKAP1 gene. This alteration results from a T to C substitution at nucleotide position 857, causing the valine (V) at amino acid position 286 to be replaced by an alanine (A). 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	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.00090	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.34	T;T
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.30		Loss of methylation at K287 (P = 0.0405);.;
MVP		0.59
MPC		0.43
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-86363271;