Genetic Variant SRGAP2:p.Arg235His (chr1-206393546-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 10.0

Publications

5 publications found

Variant links:

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]

SRGAP2 links:

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ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD2 exomes

AF:

0.00294

AC:

617

AN:

209880

AF XY:

0.00271

show subpopulations

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:

AN:

626626

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

341334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17614

American (AMR)

AF:

0.00

AC:

AN:

43364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20926

East Asian (EAS)

AF:

0.00

AC:

AN:

36056

South Asian (SAS)

AF:

0.00

AC:

AN:

69182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4140

European-Non Finnish (NFE)

AF:

0.00000286

AC:

AN:

349244

Other (OTH)

AF:

0.0000303

AC:

AN:

32996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00856

Hom.:

ExAC

AF:

0.0140

AC:

1689

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0097

MetaSVM

Uncertain

-0.21

PhyloP100

PrimateAI

Pathogenic

0.89

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.34

ClinPred

0.056

GERP RS

5.6

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over