NM_001385994.1:c.2743A>G

Variant names:

• chr5-137940296-T-C
• NM_001385994.1:c.2743A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001385994.1(FAM13B):​c.2743A>G​(p.Lys915Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAM13B NM_001385994.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385994.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM13B	NM_001385994.1	MANE Select	c.2743A>G	p.Lys915Glu	missense	Exon 24 of 24	NP_001372923.1	A0A8I5KSB9
	PKD2L2	NM_001300921.2	MANE Select	c.*18-2088T>C		intron	N/A	NP_001287850.1	Q9NZM6-1
	FAM13B	NM_001385921.1		c.2677A>G	p.Lys893Glu	missense	Exon 24 of 24	NP_001372850.1	A0A2X0SG06

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM13B	ENST00000689681.1	MANE Select	c.2743A>G	p.Lys915Glu	missense	Exon 24 of 24	ENSP00000509788.1	A0A8I5KSB9
	FAM13B	ENST00000033079.7	TSL:1	c.2677A>G	p.Lys893Glu	missense	Exon 23 of 23	ENSP00000033079.3	Q9NYF5-1
	FAM13B	ENST00000420893.6	TSL:1	c.2593A>G	p.Lys865Glu	missense	Exon 22 of 22	ENSP00000388521.2	Q9NYF5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456662 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725098

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107350

Other (OTH) AF: 0.00 AC: 0 AN: 60188

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.40		Loss of methylation at K893 (P = 0.0033)
MVP		0.51
MPC		0.64
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.60
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr5-137275985;