2-96878426-G-A

Position:

• chr2-96878426-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122646.3(FAM178B):​c.1844C>T​(p.Pro615Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM178B NM_001122646.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

Genes affected

FAM178B (HGNC:28036): (family with sequence similarity 178 member B)

FAM178B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2337116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM178B	NM_001122646.3	c.1844C>T	p.Pro615Leu	missense_variant	15/17	ENST00000490605.3	NP_001116118.2
FAM178B	NM_001172667.2	c.221C>T	p.Pro74Leu	missense_variant	3/5		NP_001166138.1
FAM178B	NM_016490.5	c.164C>T	p.Pro55Leu	missense_variant	3/5		NP_057574.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM178B	ENST00000490605.3	c.1844C>T	p.Pro615Leu	missense_variant	15/17	5	NM_001122646.3	ENSP00000429896.1
FAM178B	ENST00000393526.6	c.164C>T	p.Pro55Leu	missense_variant	3/5	1		ENSP00000377160.2
FAM178B	ENST00000470789.5	n.276C>T		non_coding_transcript_exon_variant	3/5	1
FAM178B	ENST00000494172.1	n.296C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 15, 2024

The c.1844C>T (p.P615L) alteration is located in exon 15 (coding exon 15) of the FAM178B gene. This alteration results from a C to T substitution at nucleotide position 1844, causing the proline (P) at amino acid position 615 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	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.041
Sift	Benign	0.055	T;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.31
MVP		0.60
MPC		0.29
ClinPred		0.92	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.28

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: rs2080300502; hg19: chr2-97544163;