rs116518022

Variant names:

• chr11-66849045-C-T
• rs116518022
• NM_001040716.2:c.3391G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4 BP6 BS1

The NM_001040716.2(PC):​c.3391G>A​(p.Val1131Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000923 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: PC NM_001040716.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 5.47
• Publications: 1 publications found

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

PC Gene-Disease associations (from GenCC):

• pyruvate carboxylase deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• pyruvate carboxylase deficiency, benign type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, severe neonatal type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.33758155).
• BP6: Variant 11-66849045-C-T is Benign according to our data. Variant chr11-66849045-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 559359.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000453 (69/152354) while in subpopulation AFR AF = 0.00166 (69/41588). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040716.2. 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
	PC	NM_001040716.2	MANE Select	c.3391G>A	p.Val1131Met	missense	Exon 23 of 23	NP_001035806.1	P11498-1
	PC	NM_000920.4		c.3391G>A	p.Val1131Met	missense	Exon 22 of 22	NP_000911.2	P11498-1
	PC	NM_001439352.1		c.3391G>A	p.Val1131Met	missense	Exon 23 of 23	NP_001426281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PC	ENST00000393960.7	TSL:5 MANE Select	c.3391G>A	p.Val1131Met	missense	Exon 23 of 23	ENSP00000377532.1	P11498-1
	PC	ENST00000393955.6	TSL:1	c.3391G>A	p.Val1131Met	missense	Exon 21 of 21	ENSP00000377527.2	P11498-1
	PC	ENST00000393958.7	TSL:1	c.3391G>A	p.Val1131Met	missense	Exon 22 of 22	ENSP00000377530.2	P11498-1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250504 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727164

African (AFR) AF: 0.00197 AC: 66 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74504

African (AFR) AF: 0.00166 AC: 69 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000657

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	Pyruvate carboxylase deficiency (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		5.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.77
MPC		1.2
ClinPred		0.33	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
Mutation Taster		=37/63	disease causing

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: rs116518022; hg19: chr11-66616516;