rs61754477

Variant names:

• chr13-23339688-G-A
• rs61754477
• NM_014363.6:c.4188C>T
• SACS p.His1396His

Your query was ambiguous. Multiple possible variants found:

• chr13-23339688-G-A
• chr13-23339688-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014363.6(SACS):​c.4188C>T​(p.His1396His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,980 control chromosomes in the GnomAD database, including 2,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (228 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1834 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.52
• Publications: 4 publications found

Genes affected

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women's Health, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 13-23339688-G-A is Benign according to our data. Variant chr13-23339688-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 283779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. 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
	SACS	NM_014363.6	MANE Select	c.4188C>T	p.His1396His	synonymous	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.4215C>T	p.His1405His	synonymous	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.3747C>T	p.His1249His	synonymous	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.4188C>T	p.His1396His	synonymous	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2431+1757C>T		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.4215C>T	p.His1405His	synonymous	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2030 AN: 152152 Hom.: 229 Cov.: 33

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0317 AC: 7953 AN: 251202 AF XY: 0.0343

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0137 AC: 20048 AN: 1461710 Hom.: 1834 Cov.: 36 AF XY: 0.0160 AC XY: 11618 AN XY: 727136

African (AFR) AF: 0.00143 AC: 48 AN: 33474

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26128

East Asian (EAS) AF: 0.242 AC: 9623 AN: 39686

South Asian (SAS) AF: 0.0963 AC: 8305 AN: 86214

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53406

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.000283 AC: 315 AN: 1111926

Other (OTH) AF: 0.0268 AC: 1620 AN: 60386

GnomAD4 genome AF: 0.0133 AC: 2027 AN: 152270 Hom.: 228 Cov.: 33 AF XY: 0.0161 AC XY: 1197 AN XY: 74462

African (AFR) AF: 0.00219 AC: 91 AN: 41558

American (AMR) AF: 0.00301 AC: 46 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1284 AN: 5170

South Asian (SAS) AF: 0.115 AC: 554 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00192 Hom.: 6

Bravo AF: 0.0113

Asia WGS AF: 0.182 AC: 631 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Charlevoix-Saguenay spastic ataxia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.2
DANN	Benign	0.44
PhyloP100		1.5
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61754477;

hg19: chr13-23913827;

COSMIC: COSV66536709;