19-2276297-C-G

Variant names:

• chr19-2276297-C-G
• rs371731431
• NM_198532.3:c.805G>C

Variant summary

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

The NM_198532.3(PEAK3):​c.805G>C​(p.Ala269Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. A269T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PEAK3 NM_198532.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.992
• Publications: 0 publications found

Genes affected

PEAK3 (HGNC:24793): (PEAK family member 3) Enables protein self-association. Involved in regulation of actin cytoskeleton organization and regulation of cell shape. Predicted to be active in actin cytoskeleton and focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000273734 (HGNC:):

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=0.107567996).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198532.3. 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
	PEAK3	NM_198532.3	MANE Select	c.805G>C	p.Ala269Pro	missense	Exon 4 of 4	NP_940934.1	Q6ZS72

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEAK3	ENST00000342063.5	TSL:2 MANE Select	c.805G>C	p.Ala269Pro	missense	Exon 4 of 4	ENSP00000345102.3	Q6ZS72
	ENSG00000273734	ENST00000621615.1	TSL:2	n.146+6553C>G		intron	N/A	ENSP00000481965.1	A0A087WYN8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440294 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716442

African (AFR) AF: 0.00 AC: 0 AN: 33130

American (AMR) AF: 0.00 AC: 0 AN: 44084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 38956

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108526

Other (OTH) AF: 0.00 AC: 0 AN: 59770

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.99
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.050
Sift	Benign	0.20	T
Sift4G	Benign	0.26	T
Polyphen		0.96	D
Vest4		0.081
MutPred		0.52		Loss of helix (P = 0.0041)
MVP		0.25
MPC		0.42
ClinPred		0.36	T
GERP RS		-1.6
Varity_R		0.28
gMVP		0.82
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: rs371731431; hg19: chr19-2276296;