chr1-206401604-C-T

Position:

• chr1-206401604-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_015326.5(SRGAP2):​c.1015C>T​(p.Pro339Ser) 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: 7.91

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, Cadd, Dann, phyloP100way_vertebrate, PrimateAI [when MetaRNN, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.3796149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRGAP2	NM_015326.5	c.1015C>T	p.Pro339Ser	missense_variant	8/23	ENST00000573034.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGAP2	ENST00000573034.8	c.1015C>T	p.Pro339Ser	missense_variant	8/23	1	NM_015326.5	P5
SRGAP2	ENST00000624873.3	c.1012C>T	p.Pro338Ser	missense_variant	7/22	1		A1
SRGAP2	ENST00000605610.5	c.1012C>T	p.Pro338Ser	missense_variant	7/20	2
SRGAP2	ENST00000419187.6	c.553C>T	p.Pro185Ser	missense_variant	5/7	5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SRGAP2-associated Neurodevelopmental Disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-1.2	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.2	N;.;.;.
Sift	Benign	0.067	T;.;.;.
Sift4G	Uncertain	0.022	D;T;T;T
Polyphen		0.40	.;.;.;B
Vest4		0.65
MutPred		0.45		.;.;.;Loss of catalytic residue at P339 (P = 0.0042);
MVP		0.45
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782657746; hg19: chr1-206574963;