11-68761622-G-C

Variant names:

• chr11-68761622-G-C
• rs115731492
• NM_001876.4:c.1941C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001876.4(CPT1A):​c.1941C>G​(p.Ala647Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,098 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A647A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00088 (26 hom.)
• Consequence: CPT1A NM_001876.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00700
• Publications: 1 publications found

Genes affected

CPT1A (HGNC:2328): (carnitine palmitoyltransferase 1A) The mitochondrial oxidation of long-chain fatty acids is initiated by the sequential action of carnitine palmitoyltransferase I (which is located in the outer membrane and is detergent-labile) and carnitine palmitoyltransferase II (which is located in the inner membrane and is detergent-stable), together with a carnitine-acylcarnitine translocase. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CPT1A Gene-Disease associations (from GenCC):

• carnitine palmitoyl transferase 1A deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-68761622-G-C is Benign according to our data. Variant chr11-68761622-G-C is described in ClinVar as Benign. ClinVar VariationId is 203653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.007 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00815 (1241/152212) while in subpopulation AFR AF = 0.0279 (1160/41530). AF 95% confidence interval is 0.0266. There are 14 homozygotes in GnomAd4. There are 592 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001876.4. 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
	CPT1A	NM_001876.4	MANE Select	c.1941C>G	p.Ala647Ala	synonymous	Exon 16 of 19	NP_001867.2	P50416-1
	CPT1A	NM_001440358.1		c.1941C>G	p.Ala647Ala	synonymous	Exon 16 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.1941C>G	p.Ala647Ala	synonymous	Exon 17 of 20	NP_001427288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	ENST00000265641.10	TSL:1 MANE Select	c.1941C>G	p.Ala647Ala	synonymous	Exon 16 of 19	ENSP00000265641.4	P50416-1
	CPT1A	ENST00000376618.6	TSL:1	c.1941C>G	p.Ala647Ala	synonymous	Exon 16 of 19	ENSP00000365803.2	P50416-2
	CPT1A	ENST00000540367.5	TSL:1	c.1941C>G	p.Ala647Ala	synonymous	Exon 15 of 18	ENSP00000439084.1	P50416-2

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152094 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00215 AC: 540 AN: 251494 AF XY: 0.00157

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000882 AC: 1289 AN: 1461886 Hom.: 26 Cov.: 32 AF XY: 0.000778 AC XY: 566 AN XY: 727246

African (AFR) AF: 0.0300 AC: 1006 AN: 33480

American (AMR) AF: 0.00192 AC: 86 AN: 44724

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

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000638 AC: 71 AN: 1112006

Other (OTH) AF: 0.00197 AC: 119 AN: 60396

GnomAD4 genome AF: 0.00815 AC: 1241 AN: 152212 Hom.: 14 Cov.: 31 AF XY: 0.00796 AC XY: 592 AN XY: 74414

African (AFR) AF: 0.0279 AC: 1160 AN: 41530

American (AMR) AF: 0.00399 AC: 61 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00250 Hom.: 3

Bravo AF: 0.00959

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Carnitine palmitoyl transferase 1A deficiency (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.0
DANN	Benign	0.40
PhyloP100		-0.0070
Mutation Taster		=84/16	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

dbSNP: rs115731492; hg19: chr11-68529090;