chr12-6935779-C-G

Variant names:

• chr12-6935779-C-G
• rs142325562
• NM_001940.4:c.512C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001940.4(ATN1):​c.512C>G​(p.Pro171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATN1 NM_001940.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.969

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19308001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATN1	NM_001940.4	c.512C>G	p.Pro171Arg	missense_variant	Exon 5 of 10	ENST00000396684.3	NP_001931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATN1	ENST00000396684.3	c.512C>G	p.Pro171Arg	missense_variant	Exon 5 of 10	1	NM_001940.4	ENSP00000379915.2
ATN1	ENST00000356654.8	c.512C>G	p.Pro171Arg	missense_variant	Exon 5 of 10	1		ENSP00000349076.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.74	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		0.63	P;P
Vest4		0.32
MutPred		0.40		Gain of catalytic residue at P166 (P = 5e-04);Gain of catalytic residue at P166 (P = 5e-04);
MVP		0.40
MPC		0.44
ClinPred		0.67	D
GERP RS		3.6
Varity_R		0.19
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs142325562; hg19: chr12-7044942;