12-109188171-CTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCT-CTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCT

Variant names:

• chr12-109188171-C-CTCCTTCCTTCCT
• rs373209583
• NM_001093.4:c.2144+61_2144+72dupTTCCTTCCTTCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001093.4(ACACB):​c.2144+61_2144+72dupTTCCTTCCTTCC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00041 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACACB NM_001093.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.839
• Publications: 0 publications found

Genes affected

ACACB (HGNC:85): (acetyl-CoA carboxylase beta) Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. [provided by RefSeq, Oct 2022]

ACACB Gene-Disease associations (from GenCC):

• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 12-109188171-C-CTCCTTCCTTCCT is Benign according to our data. Variant chr12-109188171-C-CTCCTTCCTTCCT is described in ClinVar as Likely_benign. ClinVar VariationId is 2049236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093.4. 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
	ACACB	NM_001093.4	MANE Select	c.2144+61_2144+72dupTTCCTTCCTTCC		intron	N/A	NP_001084.3	O00763-1
	ACACB	NM_001412734.1		c.2144+61_2144+72dupTTCCTTCCTTCC		intron	N/A	NP_001399663.1	O00763-1
	ACACB	NM_001412735.1		c.2144+61_2144+72dupTTCCTTCCTTCC		intron	N/A	NP_001399664.1	O00763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	ENST00000338432.12	TSL:1 MANE Select	c.2144+9_2144+10insTCCTTCCTTCCT		intron	N/A	ENSP00000341044.7	O00763-1
	ACACB	ENST00000377848.7	TSL:1	c.2144+9_2144+10insTCCTTCCTTCCT		intron	N/A	ENSP00000367079.3	O00763-1
	ACACB	ENST00000377854.9	TSL:5	c.-1859+9_-1859+10insTCCTTCCTTCCT		intron	N/A	ENSP00000367085.6	F8W8T8

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 199 AN: 105040 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00522

Gnomad SAS AF: 0.000824

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000300

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000407 AC: 509 AN: 1251962 Hom.: 4 Cov.: 0 AF XY: 0.000426 AC XY: 263 AN XY: 617858

African (AFR) AF: 0.00172 AC: 48 AN: 27902

American (AMR) AF: 0.00120 AC: 43 AN: 35894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21920

East Asian (EAS) AF: 0.00570 AC: 189 AN: 33172

South Asian (SAS) AF: 0.00108 AC: 77 AN: 71436

European-Finnish (FIN) AF: 0.000420 AC: 19 AN: 45272

Middle Eastern (MID) AF: 0.000452 AC: 2 AN: 4420

European-Non Finnish (NFE) AF: 0.0000978 AC: 94 AN: 961364

Other (OTH) AF: 0.000731 AC: 37 AN: 50582

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00190 AC: 200 AN: 105130 Hom.: 3 Cov.: 0 AF XY: 0.00199 AC XY: 99 AN XY: 49728

African (AFR) AF: 0.00477 AC: 133 AN: 27904

American (AMR) AF: 0.00228 AC: 23 AN: 10076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2698

East Asian (EAS) AF: 0.00524 AC: 17 AN: 3246

South Asian (SAS) AF: 0.000822 AC: 2 AN: 2432

European-Finnish (FIN) AF: 0.00152 AC: 10 AN: 6572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.000300 AC: 15 AN: 50016

Other (OTH) AF: 0.00 AC: 0 AN: 1330

Alfa AF: 0.00 Hom.: 759

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs373209583; hg19: chr12-109625976;