12-63984086-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020762.4(SRGAP1):c.207G>C(p.Lys69Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

Genes affected

SRGAP1 (HGNC:17382): (SLIT-ROBO Rho GTPase activating protein 1) The protein encoded by this gene is a GTPase activator, working with the GTPase CDC42 to negatively regulate neuronal migration. The encoded protein interacts with the transmembrane receptor ROBO1 to inactivate CDC42. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRGAP1	NM_020762.4	c.207G>C	p.Lys69Asn	missense_variant	2/22	ENST00000355086.8
SRGAP1	NM_001346201.2	c.207G>C	p.Lys69Asn	missense_variant	2/22
SRGAP1	XM_024449096.2	c.207G>C	p.Lys69Asn	missense_variant	2/14
SRGAP1	XM_024449097.2	c.207G>C	p.Lys69Asn	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGAP1	ENST00000355086.8	c.207G>C	p.Lys69Asn	missense_variant	2/22	1	NM_020762.4	A1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383632 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 687918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.39e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.207G>C (p.K69N) alteration is located in exon 2 (coding exon 2) of the SRGAP1 gene. This alteration results from a G to C substitution at nucleotide position 207, causing the lysine (K) at amino acid position 69 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.4	D;.;D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.38	B;P;P
Vest4		0.93
MutPred		0.57		Loss of methylation at K69 (P = 0.0113);.;.;
MVP		0.68
MPC		1.4
ClinPred		0.97	D
GERP RS		1.2
Varity_R		0.58
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-64377866;