NM_001301202.2:c.2045G>C

Variant names:

• chr12-113104005-C-G
• NM_001301202.2:c.2045G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001301202.2(RASAL1):​c.2045G>C​(p.Cys682Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASAL1 NM_001301202.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

Genes affected

RASAL1 (HGNC:9873): (RAS protein activator like 1) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. These proteins stimulate the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. This particular family member contains domains which are characteristic of the GAP1 subfamily of RasGAP proteins but, in contrast to the other GAP1 family members, this protein is strongly and selectively expressed in endocrine tissues. Alternatively spliced transcript variants that encode different isoforms have been described [provided by RefSeq, Jul 2010]

RASAL1 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000295497 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301202.2. 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
	RASAL1	NM_001301202.2	MANE Select	c.2045G>C	p.Cys682Ser	missense	Exon 18 of 21	NP_001288131.1	O95294-4
	RASAL1	NM_001193520.2		c.2048G>C	p.Cys683Ser	missense	Exon 19 of 22	NP_001180449.1	O95294-3
	RASAL1	NM_001394081.1		c.2048G>C	p.Cys683Ser	missense	Exon 18 of 21	NP_001381010.1	O95294-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASAL1	ENST00000548055.2	TSL:1 MANE Select	c.2045G>C	p.Cys682Ser	missense	Exon 18 of 21	ENSP00000448510.1	O95294-4
	RASAL1	ENST00000546530.5	TSL:1	c.2048G>C	p.Cys683Ser	missense	Exon 19 of 22	ENSP00000450244.1	O95294-3
	RASAL1	ENST00000261729.9	TSL:1	c.2042G>C	p.Cys681Ser	missense	Exon 19 of 22	ENSP00000261729.5	O95294-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.55
Sift	Benign	0.26	T
Sift4G	Uncertain	0.028	D
Polyphen		0.94	P
Vest4		0.64
MutPred		0.61		Loss of catalytic residue at C681 (P = 0.0026)
MVP		0.96
MPC		0.51
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.28
gMVP		0.47
Mutation Taster		=88/12	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

hg19: chr12-113541810;