20-20472898-C-T

Variant names:

• chr20-20472898-C-T
• rs201178329
• NM_020343.4:c.5426G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020343.4(RALGAPA2):​c.5426G>A​(p.Ser1809Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: RALGAPA2 NM_020343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

Genes affected

RALGAPA2 (HGNC:16207): (Ral GTPase activating protein catalytic subunit alpha 2) Predicted to enable GTPase activator activity and protein heterodimerization activity. Predicted to be involved in activation of GTPase activity. Predicted to act upstream of or within Ral protein signal transduction; regulation of exocyst localization; and regulation of protein localization. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05188471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RALGAPA2	NM_020343.4	c.5426G>A	p.Ser1809Asn	missense_variant	Exon 37 of 40	ENST00000202677.12	NP_065076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RALGAPA2	ENST00000202677.12	c.5426G>A	p.Ser1809Asn	missense_variant	Exon 37 of 40	5	NM_020343.4	ENSP00000202677.6
RALGAPA2	ENST00000430436.5	c.4874G>A	p.Ser1625Asn	missense_variant	Exon 31 of 33	5		ENSP00000400085.1
RALGAPA2	ENST00000427175.2	c.656G>A	p.Ser219Asn	missense_variant	Exon 6 of 6	2		ENSP00000388695.1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000720 AC: 179 AN: 248692 Hom.: 0 AF XY: 0.000786 AC XY: 106 AN XY: 134888

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.00119 AC: 1740 AN: 1461274 Hom.: 1 Cov.: 30 AF XY: 0.00113 AC XY: 825 AN XY: 726920

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74496

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.000719 AC: 87

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.00154

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5426G>A (p.S1809N) alteration is located in exon 37 (coding exon 37) of the RALGAPA2 gene. This alteration results from a G to A substitution at nucleotide position 5426, causing the serine (S) at amino acid position 1809 to be replaced by an asparagine (N). 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	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	0.71	N;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.20	T;.
Sift4G	Benign	0.50	T;T
Polyphen		0.0040	B;.
Vest4		0.69
MVP		0.66
MPC		0.092
ClinPred		0.042	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs201178329; hg19: chr20-20453542;