NM_015326.5:c.920A>C

Variant names:

• chr1-206401509-A-C
• rs1350526469
• NM_015326.5:c.920A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_015326.5(SRGAP2):​c.920A>C​(p.His307Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SRGAP2 NM_015326.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

SRGAP2 (HGNC:19751): (SLIT-ROBO Rho GTPase activating protein 2) This locus encodes a member of the SLIT-ROBO Rho GTPase activating protein family. The encoded protein stimulates GTPase activity of Rac1, and plays a role in cortical neuron development. This locus has several paralogs on human chromosome 1 resulting from segmental duplication. While this locus itself is conserved among various species, the paralogs are found only in the genus Homo, and not in the genomes of non-human great apes. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Jul 2014]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, Cadd, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI [when MetaRNN, REVEL was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.4079986).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015326.5. 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
	SRGAP2	NM_015326.5	MANE Select	c.920A>C	p.His307Pro	missense	Exon 8 of 23	NP_056141.2	O75044
	SRGAP2	NM_001170637.4		c.917A>C	p.His306Pro	missense	Exon 8 of 23	NP_001164108.1	B7ZM87
	SRGAP2	NM_001377444.1		c.920A>C	p.His307Pro	missense	Exon 8 of 24	NP_001364373.1	A0A1S5UZH8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRGAP2	ENST00000573034.8	TSL:1 MANE Select	c.920A>C	p.His307Pro	missense	Exon 8 of 23	ENSP00000459615.2	O75044
	SRGAP2	ENST00000624873.3	TSL:1	c.917A>C	p.His306Pro	missense	Exon 7 of 22	ENSP00000485517.1	B7ZM87
	SRGAP2	ENST00000934486.1		c.917A>C	p.His306Pro	missense	Exon 8 of 24	ENSP00000604545.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
Sift4G	Benign	0.10	T
Polyphen		0.61	P
Vest4		0.67
MutPred		0.29		Gain of glycosylation at S305 (P = 0.0728)
MVP		0.43
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.82
gMVP		0.86
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1350526469; hg19: chr1-206574868;