5-137940304-C-T

Variant names:

• chr5-137940304-C-T
• rs1761256175
• NM_001385994.1:c.2735G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001385994.1(FAM13B):​c.2735G>A​(p.Arg912Lys) 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 1,457,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM13B NM_001385994.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.366

Genes affected

FAM13B (HGNC:1335): (family with sequence similarity 13 member B) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PKD2L2 (HGNC:9012): (polycystin 2 like 2, transient receptor potential cation channel) Predicted to enable calcium channel activity. Predicted to be involved in detection of mechanical stimulus. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056271613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM13B	NM_001385994.1	c.2735G>A	p.Arg912Lys	missense_variant	Exon 24 of 24	ENST00000689681.1	NP_001372923.1
PKD2L2	NM_001300921.2	c.*18-2080C>T		intron_variant	Intron 14 of 14	ENST00000508883.6	NP_001287850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM13B	ENST00000689681.1	c.2735G>A	p.Arg912Lys	missense_variant	Exon 24 of 24		NM_001385994.1	ENSP00000509788.1
PKD2L2	ENST00000508883.6	c.*18-2080C>T		intron_variant	Intron 14 of 14	1	NM_001300921.2	ENSP00000424725.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457094 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725218

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2669G>A (p.R890K) alteration is located in exon 23 (coding exon 21) of the FAM13B gene. This alteration results from a G to A substitution at nucleotide position 2669, causing the arginine (R) at amino acid position 890 to be replaced by a lysine (K). 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	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.14	B;.;B
Vest4		0.078
MutPred		0.22		Gain of methylation at R890 (P = 0.0354);.;.;
MVP		0.12
MPC		0.11
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.083
gMVP		0.098

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: rs1761256175; hg19: chr5-137275993; COSMIC: COSV50374757; COSMIC: COSV50374757;