7-92307558-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_019004.2(ANKIB1):c.388C>G(p.Gln130Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. Q130H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ANKIB1 NM_019004.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.73

Genes affected

ANKIB1 (HGNC:22215): (ankyrin repeat and IBR domain containing 1) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Predicted to be involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; protein polyubiquitination; and ubiquitin-dependent protein catabolic process. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ANKIB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.12875262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKIB1	NM_019004.2	c.388C>G	p.Gln130Glu	missense_variant	3/20	ENST00000265742.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKIB1	ENST00000265742.8	c.388C>G	p.Gln130Glu	missense_variant	3/20	1	NM_019004.2	P1
ANKIB1	ENST00000442183.1	c.388C>G	p.Gln130Glu	missense_variant	3/3	4
ANKIB1	ENST00000439883.1	c.202C>G	p.Gln68Glu	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.388C>G (p.Q130E) alteration is located in exon 3 (coding exon 2) of the ANKIB1 gene. This alteration results from a C to G substitution at nucleotide position 388, causing the glutamine (Q) at amino acid position 130 to be replaced by a glutamic acid (E). 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	0.064
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	0.0030
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.090	N;.
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.043
Sift	Benign	0.20	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.082
MutPred		0.33		Loss of MoRF binding (P = 0.0705);Loss of MoRF binding (P = 0.0705);
MVP		0.45
MPC		0.80
ClinPred		0.49	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.30

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: rs1463525996; hg19: chr7-91936872;