14-95196654-A-G

Position:

• chr14-95196654-A-G

Variant summary

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

The NM_024734.4(CLMN):​c.2552T>C​(p.Leu851Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLMN NM_024734.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.475

Genes affected

CLMN (HGNC:19972): (calmin) Predicted to enable actin filament binding activity. Predicted to be involved in negative regulation of cell population proliferation and nuclear migration. Predicted to act upstream of or within neuron projection development. Predicted to be integral component of membrane. Predicted to be part of meiotic nuclear membrane microtubule tethering complex. Predicted to be active in cytoplasm and nuclear outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLMN	NM_024734.4	c.2552T>C	p.Leu851Pro	missense_variant	10/13	ENST00000298912.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLMN	ENST00000298912.9	c.2552T>C	p.Leu851Pro	missense_variant	10/13	1	NM_024734.4	P1
CLMN	ENST00000556454.1	n.1916T>C		non_coding_transcript_exon_variant	4/6	2

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

Feb 26, 2024

The c.2552T>C (p.L851P) alteration is located in exon 10 (coding exon 10) of the CLMN gene. This alteration results from a T to C substitution at nucleotide position 2552, causing the leucine (L) at amino acid position 851 to be replaced by a proline (P). 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	0.10
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.12		Gain of glycosylation at L851 (P = 0.0385);
MVP		0.95
MPC		0.51
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.46
gMVP		0.33

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: rs1896723747; hg19: chr14-95662991;