1-178283614-A-C

Variant names:

• chr1-178283614-A-C
• NM_170692.4:c.253A>C

Variant summary

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

The NM_170692.4(RASAL2):​c.253A>C​(p.Thr85Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 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: 6.8e-7 (0 hom.)
• Consequence: RASAL2 NM_170692.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60

Genes affected

RASAL2 (HGNC:9874): (RAS protein activator like 2) This gene encodes a protein that contains the GAP-related domain (GRD), a characteristic domain of GTPase-activating proteins (GAPs). GAPs function as activators of Ras superfamily of small GTPases. The protein encoded by this gene is able to complement the defective RasGAP function in a yeast system. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 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 rank	MANE	Protein	UniProt
RASAL2	NM_170692.4	c.253A>C	p.Thr85Pro	missense_variant	Exon 2 of 18	ENST00000367649.8	NP_733793.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL2	ENST00000367649.8	c.253A>C	p.Thr85Pro	missense_variant	Exon 2 of 18	1	NM_170692.4	ENSP00000356621.3
RASAL2	ENST00000696605.1	c.640A>C	p.Thr214Pro	missense_variant	Exon 2 of 18			ENSP00000512749.1
RASAL2	ENST00000465723.1	n.577A>C		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253A>C (p.T85P) alteration is located in exon 2 (coding exon 2) of the RASAL2 gene. This alteration results from a A to C substitution at nucleotide position 253, causing the threonine (T) at amino acid position 85 to be replaced by a proline (P). 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	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	-0.056
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.16	T
Vest4		0.64
MutPred		0.54		Gain of glycosylation at T85 (P = 0.0284);
MVP		0.32
MPC		0.73
ClinPred		0.98	D
GERP RS		4.2
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-178252749;