12-64042931-C-G

Variant names:

• chr12-64042931-C-G
• rs201075531
• NM_020762.4:c.631C>G

Variant summary

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

The NM_020762.4(SRGAP1):​c.631C>G​(p.Arg211Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R211W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.796
• Publications: 3 publications found

Genes affected

SRGAP1 (HGNC:17382): (SLIT-ROBO Rho GTPase activating protein 1) The protein encoded by this gene is a GTPase activator, working with the GTPase CDC42 to negatively regulate neuronal migration. The encoded protein interacts with the transmembrane receptor ROBO1 to inactivate CDC42. [provided by RefSeq, Sep 2016]

SRGAP1 Gene-Disease associations (from GenCC):

• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• thyroid cancer, nonmedullary, 2

  Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000255886 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020762.4. 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
	SRGAP1	NM_020762.4	MANE Select	c.631C>G	p.Arg211Gly	missense	Exon 5 of 22	NP_065813.1	Q7Z6B7-1
	SRGAP1	NM_001346201.2		c.631C>G	p.Arg211Gly	missense	Exon 5 of 22	NP_001333130.1	Q7Z6B7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRGAP1	ENST00000355086.8	TSL:1 MANE Select	c.631C>G	p.Arg211Gly	missense	Exon 5 of 22	ENSP00000347198.3	Q7Z6B7-1
	SRGAP1	ENST00000543397.1	TSL:1	n.1986C>G		non_coding_transcript_exon	Exon 4 of 21
	SRGAP1	ENST00000875666.1		c.568C>G	p.Arg190Gly	missense	Exon 4 of 21	ENSP00000545725.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.80
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.078	B
Vest4		0.70
MutPred		0.26		Loss of methylation at K216 (P = 0.0537)
MVP		0.69
MPC		0.91
ClinPred		0.97	D
GERP RS		2.2
Varity_R		0.39
gMVP		0.56
Mutation Taster		=39/61	disease causing

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: rs201075531; hg19: chr12-64436711;