rs368218879

Variant names:

• chr6-16327681-C-A
• rs368218879
• NM_001128164.2:c.630G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-16327681-C-A
• chr6-16327681-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001128164.2(ATXN1):​c.630G>T​(p.Gln210His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 116,300 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN1 NM_001128164.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.00
• Publications: 11 publications found

Genes affected

ATXN1 (HGNC:10548): (ataxin 1) The autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum, brain stem and spinal cord. Clinically, ADCA has been divided into three groups: ADCA types I-III. ADCAI is genetically heterogeneous, with five genetic loci, designated spinocerebellar ataxia (SCA) 1, 2, 3, 4 and 6, being assigned to five different chromosomes. ADCAII, which always presents with retinal degeneration (SCA7), and ADCAIII often referred to as the `pure' cerebellar syndrome (SCA5), are most likely homogeneous disorders. Several SCA genes have been cloned and shown to contain CAG repeats in their coding regions. ADCA is caused by the expansion of the CAG repeats, producing an elongated polyglutamine tract in the corresponding protein. The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations. The function of the ataxins is not known. This locus has been mapped to chromosome 6, and it has been determined that the diseased allele contains 40-83 CAG repeats, compared to 6-39 in the normal allele, and is associated with spinocerebellar ataxia type 1 (SCA1). Alternative splicing results in multiple transcript variants, with one variant encoding multiple distinct proteins, ATXN1 and Alt-ATXN1, due to the use of overlapping alternate reading frames. [provided by RefSeq, Nov 2017]

ATXN1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.09375334).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128164.2. 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
	ATXN1	NM_001128164.2	MANE Select	c.630G>T	p.Gln210His	missense	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.630G>T	p.Gln210His	missense	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*43G>T		3_prime_UTR	Exon 8 of 9	NP_001344786.1	A0A2R8YCF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATXN1	ENST00000436367.6	TSL:1 MANE Select	c.630G>T	p.Gln210His	missense	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.630G>T	p.Gln210His	missense	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*43G>T		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.000129 AC: 15 AN: 116300 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000925

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: 0.000115

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000157 AC: 2 AN: 127286 AF XY: 0.0000139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000336

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000388 AC: 51 AN: 1314922 Hom.: 0 Cov.: 96 AF XY: 0.0000396 AC XY: 26 AN XY: 656322

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000965 AC: 2 AN: 20736

American (AMR) AF: 0.00 AC: 0 AN: 36428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.000103 AC: 3 AN: 29224

South Asian (SAS) AF: 0.0000267 AC: 2 AN: 74982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4854

European-Non Finnish (NFE) AF: 0.0000418 AC: 43 AN: 1028246

Other (OTH) AF: 0.0000188 AC: 1 AN: 53064

⚠️ 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 AF: 0.000129 AC: 15 AN: 116300 Hom.: 0 Cov.: 32 AF XY: 0.000125 AC XY: 7 AN XY: 56144

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000281 AC: 7 AN: 24926

American (AMR) AF: 0.0000925 AC: 1 AN: 10806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3132

East Asian (EAS) AF: 0.00 AC: 0 AN: 2542

South Asian (SAS) AF: 0.00 AC: 0 AN: 3356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000115 AC: 7 AN: 60676

Other (OTH) AF: 0.00 AC: 0 AN: 1568

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00312 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Spinocerebellar ataxia type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.1
DANN	Benign	0.73
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.012
Sift	Benign	0.034	D
Sift4G	Uncertain	0.012	D
Vest4		0.17
MutPred		0.21		Loss of MoRF binding (P = 0.5121)
MVP		0.68
MPC		0.39
ClinPred		0.11	T
Varity_R		0.12
gMVP		0.43
Mutation Taster		=100/0	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: rs368218879; hg19: chr6-16327912; COSMIC: COSV55211860; COSMIC: COSV55211860;