12-49295621-G-C

Variant names:

• chr12-49295621-G-C
• rs58599399
• NM_006262.4:c.421G>C

Variant summary

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

The NM_006262.4(PRPH):​c.421G>C​(p.Asp141His) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,393,282 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. D141Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PRPH NM_006262.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80
• Publications: 0 publications found

Genes affected

PRPH (HGNC:9461): (peripherin) This gene encodes a cytoskeletal protein found in neurons of the peripheral nervous system. The encoded protein is a type III intermediate filament protein with homology to other cytoskeletal proteins such as desmin, and is a different protein that the peripherin found in photoreceptors. Mutations in this gene have been associated with susceptibility to amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2008]

TROAP-AS1 (HGNC:55453): (TROAP and PRPH antisense RNA 1)

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_006262.4. 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
	PRPH	NM_006262.4	MANE Select	c.421G>C	p.Asp141His	missense	Exon 1 of 9	NP_006253.2
	TROAP-AS1	NR_120449.1		n.2451C>G		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH	ENST00000257860.9	TSL:1 MANE Select	c.421G>C	p.Asp141His	missense	Exon 1 of 9	ENSP00000257860.4	P41219-1
	PRPH	ENST00000451891.4	TSL:5	c.100-18G>C		intron	N/A	ENSP00000408897.4	F8W835
	TROAP-AS1	ENST00000553259.1	TSL:2	n.2451C>G		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393282 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 687148

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.00 AC: 0 AN: 35600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25064

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077752

Other (OTH) AF: 0.00 AC: 0 AN: 57828

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.53
Sift	Benign	0.060	T
Sift4G	Benign	0.092	T
Polyphen		0.94	P
Vest4		0.25
MutPred		0.58		Gain of catalytic residue at L143 (P = 5e-04)
MVP		0.89
MPC		1.5
ClinPred		0.90	D
GERP RS		4.7
PromoterAI		-0.021	Neutral
Varity_R		0.26
gMVP		0.31
Mutation Taster		=57/43	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: rs58599399; hg19: chr12-49689404;