chr10-114297289-C-G

Variant names:

• chr10-114297289-C-G
• rs1589899072
• NM_001001936.3:c.2238G>C

Variant summary

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

The NM_001001936.3(AFAP1L2):​c.2238G>C​(p.Lys746Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K746R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AFAP1L2 NM_001001936.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

Genes affected

AFAP1L2 (HGNC:25901): (actin filament associated protein 1 like 2) Enables SH2 domain binding activity; SH3 domain binding activity; and protein tyrosine kinase activator activity. Involved in several processes, including positive regulation of epidermal growth factor receptor signaling pathway; regulation of gene expression; and regulation of mitotic cell cycle. Located in cytosol and plasma 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, 0.745

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001936.3. 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
	AFAP1L2	NM_001001936.3	MANE Select	c.2238G>C	p.Lys746Asn	missense	Exon 17 of 19	NP_001001936.1	Q8N4X5-1
	AFAP1L2	NM_001287824.2		c.2397G>C	p.Lys799Asn	missense	Exon 18 of 20	NP_001274753.1
	AFAP1L2	NM_001351065.2		c.2322G>C	p.Lys774Asn	missense	Exon 18 of 20	NP_001337994.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AFAP1L2	ENST00000304129.9	TSL:1 MANE Select	c.2238G>C	p.Lys746Asn	missense	Exon 17 of 19	ENSP00000303042.4	Q8N4X5-1
	AFAP1L2	ENST00000369271.7	TSL:1	c.2238G>C	p.Lys746Asn	missense	Exon 17 of 19	ENSP00000358276.3	Q8N4X5-2
	AFAP1L2	ENST00000941481.1		c.2481G>C	p.Lys827Asn	missense	Exon 19 of 21	ENSP00000611540.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

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	0.86
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.72
MPC		0.71
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.65
gMVP		0.32
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs1589899072; hg19: chr10-116057048;