14-95191685-G-A

Position:

• chr14-95191685-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024734.4(CLMN):​c.2888C>T​(p.Pro963Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,612,860 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0098 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (22 hom.)
• Consequence: CLMN NM_024734.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00100

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025978386).
• BP6: Variant 14-95191685-G-A is Benign according to our data. Variant chr14-95191685-G-A is described in ClinVar as [Benign]. Clinvar id is 786255.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00985 (1499/152232) while in subpopulation AFR AF= 0.0345 (1434/41514). AF 95% confidence interval is 0.0331. There are 23 homozygotes in gnomad4. There are 686 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLMN	NM_024734.4	c.2888C>T	p.Pro963Leu	missense_variant	13/13	ENST00000298912.9
CLMN	XM_011537158.2	c.2981C>T	p.Pro994Leu	missense_variant	14/14
CLMN	XM_017021646.2	c.2921C>T	p.Pro974Leu	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLMN	ENST00000298912.9	c.2888C>T	p.Pro963Leu	missense_variant	13/13	1	NM_024734.4	P1

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1497 AN: 152114 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00245 AC: 611 AN: 249504 Hom.: 11 AF XY: 0.00170 AC XY: 230 AN XY: 134976

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000952 AC: 1391 AN: 1460628 Hom.: 22 Cov.: 31 AF XY: 0.000762 AC XY: 554 AN XY: 726640

Gnomad4 AFR exome AF: 0.0341

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00985 AC: 1499 AN: 152232 Hom.: 23 Cov.: 32 AF XY: 0.00922 AC XY: 686 AN XY: 74434

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00163 Hom.: 10

Bravo AF: 0.0109

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00306 AC: 372

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;D
REVEL	Benign	0.19
Sift	Benign	0.23	T;T
Sift4G	Uncertain	0.019	D;D
Polyphen		0.032	B;.
Vest4		0.062
MVP		0.77
MPC		0.11
ClinPred		0.011	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs10149705; hg19: chr14-95658022; COSMIC: COSV104599437; COSMIC: COSV104599437;