CP p.Gly195Arg

Variant names:

• chr3-149210191-C-G
• NM_000096.4:c.583G>C
• CP p.Gly195Arg

Your query was ambiguous. Multiple possible variants found:

• chr3-149210191-C-G
• chr3-149210191-C-T
• chr3-149210189-TCC-ACG
• chr3-149210189-TCC-GCG
• chr3-149210189-TCC-CCG
• chr3-149210189-TCC-CCT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_Strong PM2 PP3_Strong

The NM_000096.4(CP):​c.583G>C​(p.Gly195Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CP NM_000096.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

CP (HGNC:2295): (ceruloplasmin) The protein encoded by this gene is a metalloprotein that binds most of the copper in plasma and is involved in the peroxidation of Fe(II)transferrin to Fe(III) transferrin. Mutations in this gene cause aceruloplasminemia, which results in iron accumulation and tissue damage, and is associated with diabetes and neurologic abnormalities. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

CP Gene-Disease associations (from GenCC):

• aceruloplasminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• disorder of iron metabolism and transport

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000096.4 (CP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000096.4. 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
	CP	NM_000096.4	MANE Select	c.583G>C	p.Gly195Arg	missense	Exon 3 of 19	NP_000087.2	P00450
	CP	NR_046371.2		n.620G>C		non_coding_transcript_exon	Exon 3 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CP	ENST00000264613.11	TSL:1 MANE Select	c.583G>C	p.Gly195Arg	missense	Exon 3 of 19	ENSP00000264613.6	P00450
	CP	ENST00000490639.5	TSL:1	n.615G>C		non_coding_transcript_exon	Exon 3 of 17
	CP	ENST00000870689.1		c.583G>C	p.Gly195Arg	missense	Exon 3 of 19	ENSP00000540748.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
gMVP		0.97
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-148927978;