10-125980253-A-G

Position:

• chr10-125980253-A-G

Variant summary

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

The NM_145235.5(FANK1):​c.106A>G​(p.Lys36Glu) 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 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)
• Consequence: FANK1 NM_145235.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.971

Genes affected

FANK1 (HGNC:23527): (fibronectin type III and ankyrin repeat domains 1) Involved in regulation of apoptotic process and regulation of transcription, DNA-templated. Located in cytosol and nucleoplasm. Colocalizes with chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FANK1 (HGNC:):

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=0.067133665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANK1	NM_145235.5	c.106A>G	p.Lys36Glu	missense_variant	2/11	ENST00000368693.6	NP_660278.3
FANK1	NM_001350939.2	c.106A>G	p.Lys36Glu	missense_variant	2/12		NP_001337868.1
FANK1	NM_001363549.2	c.88A>G	p.Lys30Glu	missense_variant	2/11		NP_001350478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANK1	ENST00000368693.6	c.106A>G	p.Lys36Glu	missense_variant	2/11	1	NM_145235.5	ENSP00000357682.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 09, 2023

The c.106A>G (p.K36E) alteration is located in exon 2 (coding exon 2) of the FANK1 gene. This alteration results from a A to G substitution at nucleotide position 106, causing the lysine (K) at amino acid position 36 to be replaced by a glutamic acid (E). 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	0.097
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.0018	T;T;.;T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.067	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.11	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.28	T;T;T;T;T;T
Sift4G	Uncertain	0.051	T;T;T;T;D;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.12
MutPred		0.43		Loss of MoRF binding (P = 0.0041);.;.;.;.;.;
MVP		0.25
MPC		0.20
ClinPred		0.092	T
GERP RS		1.2
Varity_R		0.070
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-127668822;