2-214948607-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173076.3(ABCA12):c.7093G>A(p.Asp2365Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,613,738 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (69 hom., cov: 31)
  • Exomes 𝑓: 0.028 (733 hom.)
• Consequence: ABCA12 NM_173076.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 2.53

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]

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023857653).
• BP6: Variant 2-214948607-C-T is Benign according to our data. Variant chr2-214948607-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214948607-C-T is described in Lovd as [Likely_benign]. Variant chr2-214948607-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0228 (3468/152196) while in subpopulation NFE AF= 0.029 (1969/68006). AF 95% confidence interval is 0.0279. There are 69 homozygotes in gnomad4. There are 1841 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA12	NM_173076.3	c.7093G>A	p.Asp2365Asn	missense_variant	47/53	ENST00000272895.12
SNHG31	NR_110292.1	n.444+660C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA12	ENST00000272895.12	c.7093G>A	p.Asp2365Asn	missense_variant	47/53	1	NM_173076.3	P1
SNHG31	ENST00000670391.1	n.438-13203C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3471 AN: 152078 Hom.: 69 Cov.: 31

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0279 AC: 7024 AN: 251338 Hom.: 165 AF XY: 0.0273 AC XY: 3710 AN XY: 135858

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0279

Gnomad ASJ exome AF: 0.00774

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.0800

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0284 AC: 41537 AN: 1461542 Hom.: 733 Cov.: 32 AF XY: 0.0283 AC XY: 20586 AN XY: 727076

Gnomad4 AFR exome AF: 0.00409

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.0753

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0228 AC: 3468 AN: 152196 Hom.: 69 Cov.: 31 AF XY: 0.0247 AC XY: 1841 AN XY: 74394

Gnomad4 AFR AF: 0.00559

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0853

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0254 Hom.: 150

Bravo AF: 0.0171

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0259 AC: 223

ExAC AF: 0.0278 AC: 3369

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0251

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 4B Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ABCA12: BP4, BS1, BS2; SNHG31: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Congenital ichthyosis of skin Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.
Eigen	Benign	-0.024
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.91	P;B
Vest4		0.093
MPC		0.61
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs726070; hg19: chr2-215813331;