chr6-16327690-C-A

Variant names:

• chr6-16327690-C-A
• rs201030692
• NM_001128164.2:c.621G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001128164.2(ATXN1):​c.621G>T​(p.Gln207His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,409,294 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: ATXN1 NM_001128164.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.06
• Publications: 20 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032785237).
• BP6: Variant 6-16327690-C-A is Benign according to our data. Variant chr6-16327690-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210502.

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.621G>T	p.Gln207His	missense	Exon 7 of 8	NP_001121636.1	P54253-1
	ATXN1	NM_000332.4		c.621G>T	p.Gln207His	missense	Exon 8 of 9	NP_000323.2	P54253-1
	ATXN1	NM_001357857.2		c.*34G>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.621G>T	p.Gln207His	missense	Exon 7 of 8	ENSP00000416360.1	P54253-1
	ATXN1	ENST00000244769.8	TSL:1	c.621G>T	p.Gln207His	missense	Exon 8 of 9	ENSP00000244769.3	P54253-1
	ATXN1	ENST00000642969.1		c.*34G>T		downstream_gene	N/A	ENSP00000493530.1	A0A2R8YCF3

Frequencies

GnomAD3 genomes AF: 0.000570 AC: 79 AN: 138632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000907

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000210

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000534

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000642 AC: 106 AN: 165226 AF XY: 0.000546

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.000542

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000831

Gnomad FIN exome AF: 0.000674

Gnomad NFE exome AF: 0.000794

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000340 AC: 432 AN: 1270584 Hom.: 1 Cov.: 35 AF XY: 0.000338 AC XY: 213 AN XY: 630484

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

African (AFR) AF: 0.00108 AC: 30 AN: 27662

American (AMR) AF: 0.000569 AC: 19 AN: 33390

Ashkenazi Jewish (ASJ) AF: 0.0000409 AC: 1 AN: 24432

East Asian (EAS) AF: 0.00121 AC: 29 AN: 24006

South Asian (SAS) AF: 0.000406 AC: 27 AN: 66528

European-Finnish (FIN) AF: 0.000735 AC: 28 AN: 38112

Middle Eastern (MID) AF: 0.00122 AC: 6 AN: 4908

European-Non Finnish (NFE) AF: 0.000266 AC: 266 AN: 999662

Other (OTH) AF: 0.000501 AC: 26 AN: 51884

⚠️ 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: 0.000570 AC: 79 AN: 138710 Hom.: 0 Cov.: 32 AF XY: 0.000518 AC XY: 35 AN XY: 67622

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

African (AFR) AF: 0.000905 AC: 35 AN: 38666

American (AMR) AF: 0.000222 AC: 3 AN: 13532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3296

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4956

South Asian (SAS) AF: 0.00125 AC: 5 AN: 4012

European-Finnish (FIN) AF: 0.000210 AC: 2 AN: 9540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000534 AC: 33 AN: 61766

Other (OTH) AF: 0.00 AC: 0 AN: 1898

⚠️ 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: 0.0174 Hom.: 0

ExAC AF: 0.00307 AC: 332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.55
DANN	Benign	0.49
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.12
MutPred		0.20		Loss of solvent accessibility (P = 0.4653)
MVP		0.60
MPC		0.39
ClinPred		0.016	T
GERP RS		-0.093
Varity_R		0.10
gMVP		0.44
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: rs201030692; hg19: chr6-16327921; COSMIC: COSV55208738; COSMIC: COSV55208738;