rs869025337

Variant names:

• chr6-105124593-G-A
• rs869025337
• NM_001199563.2:c.602C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-105124593-G-A
• chr6-105124593-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001199563.2(POPDC1):​c.602C>T​(p.Ser201Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005325834: Published functional studies demonstrate a damaging effect (PMID:26642364, 36624536)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S201C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: POPDC1 NM_001199563.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.92
• Publications: 20 publications found

Genes affected

POPDC1 (HGNC:1152): (blood vessel epicardial substance) This gene encodes a member of the POP family of proteins containing three putative transmembrane domains. This gene is expressed in cardiac and skeletal muscle and may play an important role in development of these tissues. The mouse ortholog may be involved in the regeneration of adult skeletal muscle and may act as a cell adhesion molecule in coronary vasculogenesis. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Dec 2010]

POPDC1 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2X

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• tetralogy of fallot

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005325834: Published functional studies demonstrate a damaging effect (PMID: 26642364, 36624536)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-105124593-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1686644.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 6-105124593-G-A is Pathogenic according to our data. Variant chr6-105124593-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 222033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199563.2. 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
	POPDC1	NM_001199563.2	MANE Select	c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	NP_001186492.1	Q8NE79
	POPDC1	NM_007073.4		c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	NP_009004.2	Q8NE79
	POPDC1	NM_147147.4		c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	NP_671488.1	Q8NE79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POPDC1	ENST00000314641.10	TSL:1 MANE Select	c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	ENSP00000313172.5	Q8NE79
	POPDC1	ENST00000336775.9	TSL:1	c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	ENSP00000337259.5	Q8NE79
	POPDC1	ENST00000446408.2	TSL:1	c.602C>T	p.Ser201Phe	missense	Exon 5 of 8	ENSP00000397310.2	Q8NE79

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460688 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111070

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2X (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.74		Loss of disorder (P = 0.018)
MVP		0.84
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.82
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs869025337; hg19: chr6-105572468; COSMIC: COSV58947039;