11-66850270-C-T

Variant names:

• chr11-66850270-C-T
• rs1555014957
• NM_001040716.2:c.2668G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001040716.2(PC):​c.2668G>A​(p.Val890Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V890F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PC NM_001040716.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 0 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-66850270-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 487339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27795953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PC	NM_001040716.2	c.2668G>A	p.Val890Ile	missense_variant	Exon 19 of 23	ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7	c.2668G>A	p.Val890Ile	missense_variant	Exon 19 of 23	5	NM_001040716.2	ENSP00000377532.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T;T;T;T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.0	.;.;.;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	0.0	.;L;L;L
PhyloP100		5.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.28	N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Vest4		0.46
ClinPred		0.71	D
GERP RS		4.9
Varity_R		0.14
Mutation Taster		=49/51	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

Other links and lift over

dbSNP: rs1555014957; hg19: chr11-66617741;