chr2-214974058-A-G

Variant names:

• chr2-214974058-A-G
• rs142349854
• NM_173076.3:c.5469-16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173076.3(ABCA12):​c.5469-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,607,148 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (185 hom.)
• Consequence: ABCA12 NM_173076.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.223
• Publications: 0 publications found

Genes affected

ABCA12 (HGNC:14637): (ATP binding cassette subfamily A member 12) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ABCA12 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Orphanet, G2P
• autosomal recessive congenital ichthyosis 4A

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-214974058-A-G is Benign according to our data. Variant chr2-214974058-A-G is described in ClinVar as Benign. ClinVar VariationId is 262830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173076.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	NM_173076.3	MANE Select	c.5469-16T>C		intron	N/A	NP_775099.2
	ABCA12	NM_015657.4		c.4515-16T>C		intron	N/A	NP_056472.2
	ABCA12	NR_103740.2		n.5967-16T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.5469-16T>C		intron	N/A	ENSP00000272895.7
	ABCA12	ENST00000389661.4	TSL:1	c.4515-16T>C		intron	N/A	ENSP00000374312.4

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1242 AN: 152164 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0140 AC: 3508 AN: 250922 AF XY: 0.0114

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00985

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00380 AC: 5535 AN: 1454866 Hom.: 185 Cov.: 28 AF XY: 0.00345 AC XY: 2498 AN XY: 724226

African (AFR) AF: 0.000750 AC: 25 AN: 33330

American (AMR) AF: 0.0818 AC: 3654 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.0186 AC: 735 AN: 39602

South Asian (SAS) AF: 0.00178 AC: 153 AN: 86096

European-Finnish (FIN) AF: 0.00918 AC: 490 AN: 53388

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.000223 AC: 247 AN: 1105792

Other (OTH) AF: 0.00377 AC: 227 AN: 60146

GnomAD4 genome AF: 0.00816 AC: 1243 AN: 152282 Hom.: 33 Cov.: 32 AF XY: 0.0103 AC XY: 766 AN XY: 74464

African (AFR) AF: 0.00116 AC: 48 AN: 41556

American (AMR) AF: 0.0628 AC: 961 AN: 15298

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

East Asian (EAS) AF: 0.0122 AC: 63 AN: 5182

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00328 Hom.: 4

Bravo AF: 0.0118

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.67
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs142349854; hg19: chr2-215838782;