5-173233216-G-C

Variant names:

• chr5-173233216-G-C
• rs937339110
• ENST00000424406:c.*281C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004387.4(NKX2-5):​c.335-7C>G variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKX2-5 NM_004387.4 splice_region, intron
• Scores: Splicing: ADA: 0.01524
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.35

Genes affected

NKX2-5 (HGNC:2488): (NK2 homeobox 5) This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-173233216-G-C is Benign according to our data. Variant chr5-173233216-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 468243.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX2-5	NM_004387.4	c.335-7C>G		splice_region_variant, intron_variant	Intron 1 of 1	ENST00000329198.5	NP_004378.1
NKX2-5	NM_001166176.2	c.*127C>G		3_prime_UTR_variant	Exon 2 of 2		NP_001159648.1
NKX2-5	NM_001166175.2	c.*281C>G		3_prime_UTR_variant	Exon 2 of 2		NP_001159647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX2-5	ENST00000424406	c.*281C>G		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000395378.2
NKX2-5	ENST00000329198.5	c.335-7C>G		splice_region_variant, intron_variant	Intron 1 of 1	1	NM_004387.4	ENSP00000327758.4
NKX2-5	ENST00000521848	c.*127C>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427906.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 24, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

c.335-7C>G in Intron 1 of the NKX2-5 gene (NM_004387.3) Chromosome position 5:172660219 G / C Found in a 4-year-old male with sick sinus syndrome and an ASD vs PFO. We classify this as a Variant of Uncertain Significance (VUS). However, we do want to offer testing to our patient’s other affected family members to see if it segregates with the sick sinus syndrome, ASDs and VSDs present in this family. Of note, it was found alongside a Likely Pathogenic variant in the SCN5A gene which can explain the sick sinus syndrome although not the ASDs and VSDs. This variant has not previously been reported in the literature in association with disease. It is not present in population databases. This variant does not change the encoded amino acid sequence of the NKX2.5 protein. The question is whether it may have an effect on splicing. According to the Invitae report, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is absent from the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is acceptable sequencing coverage at this site. Over 90% of individuals are covered at 10x and 75% are covered at 20x, with mean coverage of 60x and median coverage of 55x. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Atrial septal defect 7 Benign:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.030		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: rs937339110; hg19: chr5-172660219;