chr7-20658647-A-C

Variant names:

• chr7-20658647-A-C
• NM_001163941.2:c.1678A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001163941.2(ABCB5):​c.1678A>C​(p.Lys560Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K560E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCB5 NM_001163941.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

Genes affected

ABCB5 (HGNC:46): (ATP binding cassette subfamily B member 5) ABCB5 belongs to the ATP-binding cassette (ABC) transporter superfamily of integral membrane proteins. These proteins participate in ATP-dependent transmembrane transport of structurally diverse molecules ranging from small ions, sugars, and peptides to more complex organic molecules (Chen et al., 2005 [PubMed 15760339]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB5	NM_001163941.2	c.1678A>C	p.Lys560Gln	missense_variant	Exon 14 of 28	ENST00000404938.7	NP_001157413.1
ABCB5	NM_178559.6	c.343A>C	p.Lys115Gln	missense_variant	Exon 5 of 19		NP_848654.3
ABCB5	NM_001163942.2	c.343A>C	p.Lys115Gln	missense_variant	Exon 5 of 6		NP_001157414.1
ABCB5	NM_001163993.3	c.343A>C	p.Lys115Gln	missense_variant	Exon 5 of 6		NP_001157465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB5	ENST00000404938.7	c.1678A>C	p.Lys560Gln	missense_variant	Exon 14 of 28	1	NM_001163941.2	ENSP00000384881.2
ABCB5	ENST00000258738.10	c.343A>C	p.Lys115Gln	missense_variant	Exon 5 of 19	1		ENSP00000258738.6
ABCB5	ENST00000443026.6	c.343A>C	p.Lys115Gln	missense_variant	Exon 5 of 6	1		ENSP00000406730.2
ABCB5	ENST00000406935.5	c.343A>C	p.Lys115Gln	missense_variant	Exon 5 of 6	2		ENSP00000383899.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1678A>C (p.K560Q) alteration is located in exon 14 (coding exon 13) of the ABCB5 gene. This alteration results from a A to C substitution at nucleotide position 1678, causing the lysine (K) at amino acid position 560 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.064	T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-0.41	.;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.86	N;N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.0030	.;B;.;.
Vest4		0.22
MutPred		0.83		.;Loss of ubiquitination at K115 (P = 0.0161);Loss of ubiquitination at K115 (P = 0.0161);Loss of ubiquitination at K115 (P = 0.0161);
MVP		0.74
MPC		0.0073
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-20698270;