1-206401509-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015326.5(SRGAP2):​c.920A>G​(p.His307Arg) 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. 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. H307P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SRGAP2 NM_015326.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21317402).

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>G	p.His307Arg	missense	Exon 8 of 23	NP_056141.2	O75044
	SRGAP2	NM_001170637.4		c.917A>G	p.His306Arg	missense	Exon 8 of 23	NP_001164108.1	B7ZM87
	SRGAP2	NM_001377444.1		c.920A>G	p.His307Arg	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>G	p.His307Arg	missense	Exon 8 of 23	ENSP00000459615.2	O75044
	SRGAP2	ENST00000624873.3	TSL:1	c.917A>G	p.His306Arg	missense	Exon 7 of 22	ENSP00000485517.1	B7ZM87
	SRGAP2	ENST00000934486.1		c.917A>G	p.His306Arg	missense	Exon 8 of 24	ENSP00000604545.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000532 AC: 1 AN: 188064 AF XY: 0.00000988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000114 AC: 6 AN: 528570 Hom.: 0 Cov.: 0 AF XY: 0.0000107 AC XY: 3 AN XY: 281642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14790

American (AMR) AF: 0.00 AC: 0 AN: 32376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18016

East Asian (EAS) AF: 0.00 AC: 0 AN: 31598

South Asian (SAS) AF: 0.00 AC: 0 AN: 57624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2444

European-Non Finnish (NFE) AF: 0.0000135 AC: 4 AN: 295946

Other (OTH) AF: 0.0000693 AC: 2 AN: 28842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000104408), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
PhyloP100		9.3
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.54	T
Polyphen		0.010	B
Vest4		0.41
MutPred		0.23		Gain of phosphorylation at S305 (P = 0.0877)
MVP		0.35
ClinPred		0.77	D
GERP RS		6.0
Varity_R		0.61
gMVP		0.71
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;