17-18316687-C-G

Position:

• chr17-18316687-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144775.3(SMCR8):​c.898C>G​(p.Pro300Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMCR8 NM_144775.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.523

Genes affected

SMCR8 (HGNC:17921): (SMCR8-C9orf72 complex subunit) Enables protein kinase binding activity and protein kinase inhibitor activity. Contributes to guanyl-nucleotide exchange factor activity. Involved in negative regulation of macromolecule metabolic process; regulation of TOR signaling; and regulation of macroautophagy. Located in chromatin; cytoplasm; and nucleoplasm. Part of guanyl-nucleotide exchange factor complex. Colocalizes with Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049916565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMCR8	NM_144775.3	c.898C>G	p.Pro300Ala	missense_variant	1/2	ENST00000406438.5	NP_658988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMCR8	ENST00000406438.5	c.898C>G	p.Pro300Ala	missense_variant	1/2	1	NM_144775.3	ENSP00000385025	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

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

Sep 27, 2021

The c.898C>G (p.P300A) alteration is located in exon 1 (coding exon 1) of the SMCR8 gene. This alteration results from a C to G substitution at nucleotide position 898, causing the proline (P) at amino acid position 300 to be replaced by an alanine (A). 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	Benign	0.077
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.91	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.029
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.28		Loss of loop (P = 0.0512);
MVP		0.12
MPC		0.047
ClinPred		0.050	T
GERP RS		2.5
Varity_R		0.045
gMVP		0.22

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: chr17-18220001;