1-206393546-G-A

Variant names:

• chr1-206393546-G-A
• rs2987927
• NM_015326.5:c.704G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BP4_Strong

The NM_015326.5(SRGAP2):​c.704G>A​(p.Arg235His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: SRGAP2 NM_015326.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 10.0
• Publications: 5 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Dann, Eigen, phyloP100way_vertebrate, PrimateAI [when BayesDel_noAF, MetaRNN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009718627).

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.704G>A	p.Arg235His	missense splice_region	Exon 7 of 23	NP_056141.2	O75044
	SRGAP2	NM_001170637.4		c.704G>A	p.Arg235His	missense splice_region	Exon 7 of 23	NP_001164108.1	B7ZM87
	SRGAP2	NM_001377444.1		c.704G>A	p.Arg235His	missense splice_region	Exon 7 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.704G>A	p.Arg235His	missense splice_region	Exon 7 of 23	ENSP00000459615.2	O75044
	SRGAP2	ENST00000624873.3	TSL:1	c.704G>A	p.Arg235His	missense splice_region	Exon 6 of 22	ENSP00000485517.1	B7ZM87
	SRGAP2	ENST00000934486.1		c.704G>A	p.Arg235His	missense splice_region	Exon 7 of 24	ENSP00000604545.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.00294 AC: 617 AN: 209880 AF XY: 0.00271

Gnomad AFR exome AF: 0.000366

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.00300

Gnomad EAS exome AF: 0.00681

Gnomad FIN exome AF: 0.000198

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00000319 AC: 2 AN: 626626 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 341334

African (AFR) AF: 0.00 AC: 0 AN: 17614

American (AMR) AF: 0.00 AC: 0 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20926

East Asian (EAS) AF: 0.00 AC: 0 AN: 36056

South Asian (SAS) AF: 0.00 AC: 0 AN: 69182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4140

European-Non Finnish (NFE) AF: 0.00000286 AC: 1 AN: 349244

Other (OTH) AF: 0.0000303 AC: 1 AN: 32996

GnomAD4 genome Cov.: 20

Alfa AF: 0.00856 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
PhyloP100		10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.75

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2987927; hg19: chr1-206566903; COSMIC: COSV55334248; COSMIC: COSV55334248;