rs2627223

Variant names:

• chr17-77498623-A-C
• rs2627223
• NM_001113491.2:c.1726A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-77498623-A-C
• chr17-77498623-A-G
• chr17-77498623-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001113491.2(SEPTIN9):​c.1726A>C​(p.Met576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. M576V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 22)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SEPTIN9 NM_001113491.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 0 publications found

Genes affected

SEPTIN9 (HGNC:7323): (septin 9) This gene is a member of the septin family involved in cytokinesis and cell cycle control. This gene is a candidate for the ovarian tumor suppressor gene. Mutations in this gene cause hereditary neuralgic amyotrophy, also known as neuritis with brachial predilection. A chromosomal translocation involving this gene on chromosome 17 and the MLL gene on chromosome 11 results in acute myelomonocytic leukemia. Multiple alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2009]

SEPTIN9 Gene-Disease associations (from GenCC):

• amyotrophic neuralgia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neuralgic amyotrophy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02241391).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113491.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	NM_001113491.2	MANE Select	c.1726A>C	p.Met576Leu	missense	Exon 12 of 12	NP_001106963.1
	SEPTIN9	NM_006640.5	MANE Plus Clinical	c.1672A>C	p.Met558Leu	missense	Exon 11 of 11	NP_006631.2
	SEPTIN9	NM_001113493.2		c.1705A>C	p.Met569Leu	missense	Exon 11 of 11	NP_001106965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEPTIN9	ENST00000427177.6	TSL:1 MANE Select	c.1726A>C	p.Met576Leu	missense	Exon 12 of 12	ENSP00000391249.1
	SEPTIN9	ENST00000329047.13	TSL:1 MANE Plus Clinical	c.1672A>C	p.Met558Leu	missense	Exon 11 of 11	ENSP00000329161.8
	SEPTIN9	ENST00000423034.6	TSL:1	c.1705A>C	p.Met569Leu	missense	Exon 11 of 11	ENSP00000405877.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147704 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458056 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 725194

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110530

Other (OTH) AF: 0.00 AC: 0 AN: 60170

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147704 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 71698

African (AFR) AF: 0.00 AC: 0 AN: 39672

American (AMR) AF: 0.00 AC: 0 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 4826

South Asian (SAS) AF: 0.00 AC: 0 AN: 4702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67454

Other (OTH) AF: 0.00 AC: 0 AN: 2046

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.6
DANN	Benign	0.62
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.070
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.017
Sift	Benign	0.40	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.20		Loss of methylation at K579 (P = 0.0581)
MVP		0.12
MPC		0.55
ClinPred		0.078	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.051
gMVP		0.54

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: rs2627223; hg19: chr17-75494705;