9-110015956-G-A

Variant names:

• chr9-110015956-G-A
• rs1291007168
• NM_007203.5:c.499G>A

Variant summary

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

The NM_007203.5(PALM2AKAP2):​c.499G>A​(p.Val167Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PALM2AKAP2 NM_007203.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.581
• Publications: 0 publications found

Genes affected

PALM2AKAP2 (HGNC:33529): (PALM2 and AKAP2 fusion) This gene belongs to the paralemmin downstream gene (PDG) family defined in PMID:22855693. Paralemmin downstream genes may have evolved contiguously with the paralemmin genes and are associated with other paralemmin paralogs in humans and several other taxa. The gene encodes three distinct protein isoforms, the PALM2 isoform, the AKAP2 isoform and the PALM2-AKAP2 isoform. The biological significance of the PALM2-AKAP2 isoforms is yet unknown. Earlier, PALM2 and AKAP2 were annotated as separate genes and PALM2-AKAP2 was annotated as a readthrough gene. [provided by RefSeq, May 2019]

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=0.10229623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALM2AKAP2	NM_007203.5	c.499G>A	p.Val167Ile	missense_variant, splice_region_variant	Exon 7 of 11	ENST00000374530.8	NP_009134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALM2AKAP2	ENST00000374530.8	c.499G>A	p.Val167Ile	missense_variant, splice_region_variant	Exon 7 of 11	2	NM_007203.5	ENSP00000363654.3
PALM2AKAP2	ENST00000302798.7	c.499G>A	p.Val167Ile	missense_variant, splice_region_variant	Exon 7 of 10	2		ENSP00000305861.7
PALM2AKAP2	ENST00000413420.5	c.1195G>A	p.Val399Ile	missense_variant, splice_region_variant	Exon 8 of 9	2		ENSP00000397839.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 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

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499G>A (p.V167I) alteration is located in exon 7 (coding exon 7) of the PALM2-AKAP2 gene. This alteration results from a G to A substitution at nucleotide position 499, causing the valine (V) at amino acid position 167 to be replaced by an isoleucine (I). 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
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.9
DANN	Benign	0.73
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		0.58
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.11	T;T;.
Sift4G	Benign	0.45	T;T;T
Vest4		0.16
MutPred		0.16		Loss of glycosylation at S162 (P = 0.146);.;Loss of glycosylation at S162 (P = 0.146);
MVP		0.19
MPC		0.080
ClinPred		0.040	T
GERP RS		0.34
gMVP		0.026
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1291007168; hg19: chr9-112778236;