chr14-95196508-T-A

Position:

• chr14-95196508-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024734.4(CLMN):​c.2698A>T​(p.Ile900Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,609,466 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (47 hom.)
• Consequence: CLMN NM_024734.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.168

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026017725).
• BP6: Variant 14-95196508-T-A is Benign according to our data. Variant chr14-95196508-T-A is described in ClinVar as [Benign]. Clinvar id is 776857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLMN	NM_024734.4	c.2698A>T	p.Ile900Phe	missense_variant	10/13	ENST00000298912.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLMN	ENST00000298912.9	c.2698A>T	p.Ile900Phe	missense_variant	10/13	1	NM_024734.4	P1
CLMN	ENST00000556454.1	n.2062A>T		non_coding_transcript_exon_variant	4/6	2
CLMN	ENST00000557696.5	n.77A>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2172 AN: 152244 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00382 AC: 945 AN: 247198 Hom.: 19 AF XY: 0.00262 AC XY: 350 AN XY: 133540

Gnomad AFR exome AF: 0.0508

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000680

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00151 AC: 2201 AN: 1457104 Hom.: 47 Cov.: 31 AF XY: 0.00131 AC XY: 946 AN XY: 724760

Gnomad4 AFR exome AF: 0.0537

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000705

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.0143 AC: 2183 AN: 152362 Hom.: 61 Cov.: 32 AF XY: 0.0140 AC XY: 1046 AN XY: 74508

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00226 Hom.: 8

Bravo AF: 0.0159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0479 AC: 211

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00460 AC: 558

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

CLMN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.5
DANN	Benign	0.79
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.62	T
Polyphen		0.87	P
Vest4		0.14
MVP		0.80
MPC		0.28
ClinPred		0.015	T
GERP RS		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.14

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: rs61750771; hg19: chr14-95662845;