8-22094472-C-A

Position:

• chr8-22094472-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022749.7(FHIP2B):​c.78C>A​(p.Phe26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FHIP2B NM_022749.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0380

Genes affected

FHIP2B (HGNC:16492): (FHF complex subunit HOOK interacting protein 2B)

FHIP2B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHIP2B	NM_022749.7	c.78C>A	p.Phe26Leu	missense_variant	2/17	ENST00000289921.8	NP_073586.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHIP2B	ENST00000289921.8	c.78C>A	p.Phe26Leu	missense_variant	2/17	5	NM_022749.7	ENSP00000289921.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459258 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 725972

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000935 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

Aug 20, 2024

The c.78C>A (p.F26L) alteration is located in exon 2 (coding exon 2) of the FAM160B2 gene. This alteration results from a C to A substitution at nucleotide position 78, causing the phenylalanine (F) at amino acid position 26 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.68		Loss of ubiquitination at K31 (P = 0.1778);
MVP		0.41
MPC		0.36
ClinPred		0.99	D
GERP RS		-1.4
Varity_R		0.77
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs957955054; hg19: chr8-21951983;