12-108788446-G-C

Variant names:

• chr12-108788446-G-C
• rs762344601
• NM_018984.4:c.2692C>G

Variant summary

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

The NM_018984.4(SSH1):​c.2692C>G​(p.Pro898Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. P898S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SSH1 NM_018984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.964
• Publications: 0 publications found

Genes affected

SSH1 (HGNC:30579): (slingshot protein phosphatase 1) The protein encoded by this gene belongs to the slingshot homolog (SSH) family of phosphatases, which regulate actin filament dynamics. The SSH proteins dephosphorylate and activate the actin binding/depolymerizing factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly. Cofilin is inactivated by kinases such as LIM domain kinase-1 (LIMK1), which may also be dephosphorylated and inactivated by SSH proteins. The SSH family thus appears to play a role in actin dynamics by reactivating cofilin proteins. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

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=0.10549751).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018984.4. 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
	SSH1	NM_018984.4	MANE Select	c.2692C>G	p.Pro898Ala	missense	Exon 15 of 15	NP_061857.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSH1	ENST00000326495.10	TSL:1 MANE Select	c.2692C>G	p.Pro898Ala	missense	Exon 15 of 15	ENSP00000315713.5	Q8WYL5-1
	SSH1	ENST00000877978.1		c.2623C>G	p.Pro875Ala	missense	Exon 14 of 14	ENSP00000548037.1
	SSH1	ENST00000546433.5	TSL:5	n.*1685C>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000447629.1	H0YHR3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419950 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 702572

⚠️ 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: 31872

American (AMR) AF: 0.00 AC: 0 AN: 38390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23174

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093166

Other (OTH) AF: 0.00 AC: 0 AN: 58376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.96
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.069
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.19	T
Polyphen		0.28	B
Vest4		0.23
MutPred		0.22		Gain of catalytic residue at K896 (P = 0)
MVP		0.26
MPC		0.33
ClinPred		0.36	T
GERP RS		4.7
Varity_R		0.070
gMVP		0.23
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs762344601; hg19: chr12-109182222;