Genetic Variant C9orf72:c.1260-21_1260-14dupTTTTTTTT (chr9-27548435-G-GAAAAAAAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_018325.5(C9orf72):c.1260-21_1260-14dupTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0098 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0051 ( 9 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.242

Publications

1 publications found

Variant links:

Genes affected

C9orf72 (HGNC:28337): (C9orf72-SMCR8 complex subunit) The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]

C9orf72 Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
progressive myoclonus epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

C9orf72 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00506 (699/138086) while in subpopulation SAS AF = 0.0184 (146/7942). AF 95% confidence interval is 0.016. There are 9 homozygotes in GnomAdExome4. There are 403 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 361 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. 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
	C9orf72	NM_018325.5	MANE Select	c.1260-21_1260-14dupTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-21_1260-14dupTTTTTTTT		intron	N/A	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.1260-21_1260-14dupTTTTTTTT	intron	N/A	ENSP00000369339.3	Q96LT7-1
C9orf72	ENST00000619707.5	TSL:1	c.1260-21_1260-14dupTTTTTTTT	intron	N/A	ENSP00000482753.1	Q96LT7-1
C9orf72	ENST00000644136.1		c.1293-21_1293-14dupTTTTTTTT	intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes

AF:

0.00982

AC:

361

AN:

36770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00870

Gnomad AMI

AF:

0.00287

Gnomad AMR

AF:

0.00388

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00480

Gnomad SAS

AF:

0.00698

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0122

GnomAD4 exome

AF:

0.00506

AC:

699

AN:

138086

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

403

AN XY:

71356

show subpopulations

African (AFR)

AF:

0.00484

AC:

AN:

3098

American (AMR)

AF:

0.00636

AC:

AN:

5658

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3726

East Asian (EAS)

AF:

0.00163

AC:

AN:

13456

South Asian (SAS)

AF:

0.0184

AC:

146

AN:

7942

European-Finnish (FIN)

AF:

0.00484

AC:

AN:

8064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

538

European-Non Finnish (NFE)

AF:

0.00442

AC:

392

AN:

88670

Other (OTH)

AF:

0.00490

AC:

AN:

6934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00982

AC:

361

AN:

36762

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

153

AN XY:

16130

show subpopulations

African (AFR)

AF:

0.00869

AC:

AN:

8168

American (AMR)

AF:

0.00387

AC:

AN:

3098

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

1360

East Asian (EAS)

AF:

0.00482

AC:

AN:

1452

South Asian (SAS)

AF:

0.00700

AC:

AN:

714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0118

AC:

244

AN:

20694

Other (OTH)

AF:

0.0122

AC:

AN:

490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.24

Splicing

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

Publications

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9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over