14-21211524-C-G

Variant names:

• chr14-21211524-C-G
• rs755824099
• NM_004500.4:c.680G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004500.4(HNRNPC):​c.680G>C​(p.Ser227Thr) variant causes a missense 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S227I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HNRNPC NM_004500.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 2 publications found

Genes affected

HNRNPC (HGNC:5035): (heterogeneous nuclear ribonucleoprotein C) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene can act as a tetramer and is involved in the assembly of 40S hnRNP particles. Multiple transcript variants encoding at least two different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06799626).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004500.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPC	NM_004500.4	MANE Select	c.680G>C	p.Ser227Thr	missense	Exon 8 of 9	NP_004491.2	P07910-2
	HNRNPC	NM_001077442.2		c.719G>C	p.Ser240Thr	missense	Exon 7 of 8	NP_001070910.1	P07910-1
	HNRNPC	NM_031314.3		c.719G>C	p.Ser240Thr	missense	Exon 8 of 9	NP_112604.2	P07910-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPC	ENST00000553300.6	TSL:1 MANE Select	c.680G>C	p.Ser227Thr	missense	Exon 8 of 9	ENSP00000450544.1	P07910-2
	HNRNPC	ENST00000554455.5	TSL:1	c.719G>C	p.Ser240Thr	missense	Exon 8 of 9	ENSP00000451291.1	P07910-1
	HNRNPC	ENST00000557201.5	TSL:1	c.719G>C	p.Ser240Thr	missense	Exon 7 of 8	ENSP00000452276.1	P07910-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.060
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.051	B
Vest4		0.17
MutPred		0.23		Gain of sheet (P = 0.0221)
MVP		0.34
ClinPred		0.073	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.12
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs755824099; hg19: chr14-21679683;