8-78601769-C-T

Variant names:

• chr8-78601769-C-T
• rs1449954071
• NM_006823.4:c.179C>T

Variant summary

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

The NM_006823.4(PKIA):​c.179C>T​(p.Ser60Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PKIA NM_006823.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

Genes affected

PKIA (HGNC:9017): (cAMP-dependent protein kinase inhibitor alpha) The protein encoded by this gene is a member of the cAMP-dependent protein kinase (PKA) inhibitor family. This protein was demonstrated to interact with and inhibit the activities of both C alpha and C beta catalytic subunits of the PKA. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

LOC105375911 (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=0.23045623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKIA	NM_006823.4	c.179C>T	p.Ser60Phe	missense_variant	Exon 4 of 4	ENST00000396418.7	NP_006814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKIA	ENST00000396418.7	c.179C>T	p.Ser60Phe	missense_variant	Exon 4 of 4	2	NM_006823.4	ENSP00000379696.2
PKIA	ENST00000518467.1	c.179C>T	p.Ser60Phe	missense_variant	Exon 3 of 3	1		ENSP00000430887.1
PKIA	ENST00000352966.9	c.179C>T	p.Ser60Phe	missense_variant	Exon 3 of 3	2		ENSP00000336552.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460220 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726394

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179C>T (p.S60F) alteration is located in exon 4 (coding exon 2) of the PKIA gene. This alteration results from a C to T substitution at nucleotide position 179, causing the serine (S) at amino acid position 60 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.42	T;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;.;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.24
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.061	T;T;T
Polyphen		0.73	P;P;P
Vest4		0.13
MutPred		0.29		Loss of phosphorylation at S60 (P = 0.0043);Loss of phosphorylation at S60 (P = 0.0043);Loss of phosphorylation at S60 (P = 0.0043);
MVP		0.48
MPC		0.35
ClinPred		0.54	D
GERP RS		5.3
Varity_R		0.17
gMVP		0.38

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: rs1449954071; hg19: chr8-79514004;