NM_144573.4:c.28-12C>T

Variant names:

• chr1-77917554-C-T
• rs1169196192
• NM_144573.4:c.28-12C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_144573.4(NEXN):​c.28-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEXN NM_144573.4 intron
• Scores: Splicing: ADA: 0.9223
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

Genes affected

NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

NEXN Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1CC

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 20

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4	c.28-12C>T		intron_variant	Intron 2 of 12	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.28-12C>T		intron_variant	Intron 2 of 12	1	NM_144573.4	ENSP00000333938.7
NEXN	ENST00000401035.7	c.28-406C>T		intron_variant	Intron 2 of 8	1		ENSP00000383814.3
NEXN	ENST00000330010.12	c.28-406C>T		intron_variant	Intron 2 of 11	2		ENSP00000327363.8
NEXN	ENST00000440324.5	c.28-12C>T		intron_variant	Intron 2 of 9	5		ENSP00000411902.1

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150916 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000978

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 246034 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000168

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000277 AC: 4 AN: 1442476 Hom.: 0 Cov.: 29 AF XY: 0.00000418 AC XY: 3 AN XY: 718452

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000304 AC: 1 AN: 32872

American (AMR) AF: 0.0000226 AC: 1 AN: 44194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39286

South Asian (SAS) AF: 0.00 AC: 0 AN: 84746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096960

Other (OTH) AF: 0.00 AC: 0 AN: 59622

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000663 AC: 1 AN: 150916 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73572

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41086

American (AMR) AF: 0.00 AC: 0 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.0000978 AC: 1 AN: 10230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67702

Other (OTH) AF: 0.00 AC: 0 AN: 2076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000746 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.71
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.55
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: rs1169196192; hg19: chr1-78383239;