NM_001199563.2:c.974A>G

Variant names:

• chr6-105101198-T-C
• NM_001199563.2:c.974A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199563.2(POPDC1):​c.974A>G​(p.His325Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POPDC1 NM_001199563.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06205368).

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.974A>G	p.His325Arg	missense	Exon 8 of 8	NP_001186492.1	Q8NE79
	POPDC1	NM_007073.4		c.974A>G	p.His325Arg	missense	Exon 8 of 8	NP_009004.2	Q8NE79
	POPDC1	NM_147147.4		c.974A>G	p.His325Arg	missense	Exon 8 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.974A>G	p.His325Arg	missense	Exon 8 of 8	ENSP00000313172.5	Q8NE79
	POPDC1	ENST00000336775.9	TSL:1	c.974A>G	p.His325Arg	missense	Exon 8 of 8	ENSP00000337259.5	Q8NE79
	POPDC1	ENST00000446408.2	TSL:1	c.974A>G	p.His325Arg	missense	Exon 8 of 8	ENSP00000397310.2	Q8NE79

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.037
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.029	B
Vest4		0.13
MutPred		0.15		Gain of MoRF binding (P = 0.0219)
MVP		0.14
MPC		0.30
ClinPred		0.38	T
GERP RS		5.5
Varity_R		0.096
gMVP		0.14
Mutation Taster		=86/14	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

hg19: chr6-105549073;