12-6934234-C-G

Variant names:

• chr12-6934234-C-G
• rs371722337
• NM_001940.4:c.86C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001940.4(ATN1):​c.86C>G​(p.Ser29Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,006 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S29L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.95
• Publications: 1 publications found

Genes affected

ATN1 (HGNC:3033): (atrophin 1) Dentatorubral pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion from 7-35 copies to 49-93 copies of a trinucleotide repeat (CAG/CAA) within this gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. Alternative splicing results in two transcripts variants that encode the same protein. [provided by RefSeq, Jul 2016]

ATN1 Gene-Disease associations (from GenCC):

• congenital hypotonia, epilepsy, developmental delay, and digital anomalies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• dentatorubral-pallidoluysian atrophy

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001940.4. 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
	ATN1	NM_001940.4	MANE Select	c.86C>G	p.Ser29Trp	missense	Exon 3 of 10	NP_001931.2	P54259
	ATN1	NM_001007026.2		c.86C>G	p.Ser29Trp	missense	Exon 3 of 10	NP_001007027.1	P54259
	ATN1	NM_001424176.1		c.86C>G	p.Ser29Trp	missense	Exon 3 of 10	NP_001411105.1	P54259

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATN1	ENST00000396684.3	TSL:1 MANE Select	c.86C>G	p.Ser29Trp	missense	Exon 3 of 10	ENSP00000379915.2	P54259
	ATN1	ENST00000356654.8	TSL:1	c.86C>G	p.Ser29Trp	missense	Exon 3 of 10	ENSP00000349076.3	P54259
	ATN1	ENST00000882240.1		c.86C>G	p.Ser29Trp	missense	Exon 3 of 11	ENSP00000552299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437006 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714936

African (AFR) AF: 0.0000318 AC: 1 AN: 31410

American (AMR) AF: 0.00 AC: 0 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 82122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4796

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106024

Other (OTH) AF: 0.00 AC: 0 AN: 59170

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.36		Gain of catalytic residue at L27 (P = 0)
MVP		0.35
MPC		0.46
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.51
gMVP		0.21
Mutation Taster		=84/16	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: rs371722337; hg19: chr12-7043397;