12-122473656-TTT-GCG

Variant names:

• chr12-122473656-TTT-GCG
• NM_017612.5:c.1963_1965delAAAinsCGC
• ZCCHC8 p.Lys655Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_017612.5(ZCCHC8):​c.1963_1965delAAAinsCGC​(p.Lys655Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K655N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZCCHC8 NM_017612.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

Genes affected

ZCCHC8 (HGNC:25265): (zinc finger CCHC-type containing 8) This gene encodes a scaffold protein which serves as an assessory factor to the nuclear RNA exosome complex. The encoded protein forms a trimeric human nuclear exosome targeting (NEXT) complex, together with hMTR4 and the RNA-binding factor RBM7 which promotes the exosomal degradation of non-coding promoter-upstream transcripts, enhancer RNAs and 3'-extended products of histone- and small nuclear RNA transcription. This complex is also thought to recruit the exosome to degrade intronic RNAs via its interaction with both the exosome and the spliceosome. It contains both an N-terminal zinc-knuckle domain and a C-terminal proline-rich domain. [provided by RefSeq, Apr 2017]

ZCCHC8 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, telomere-related, 5

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017612.5. 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
	ZCCHC8	NM_017612.5	MANE Select	c.1963_1965delAAAinsCGC	p.Lys655Arg	missense	N/A	NP_060082.2
	ZCCHC8	NM_001350935.2		c.1732_1734delAAAinsCGC	p.Lys578Arg	missense	N/A	NP_001337864.1
	ZCCHC8	NM_001350936.2		c.1666_1668delAAAinsCGC	p.Lys556Arg	missense	N/A	NP_001337865.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC8	ENST00000633063.3	TSL:1 MANE Select	c.1963_1965delAAAinsCGC	p.Lys655Arg	missense	N/A	ENSP00000488055.1	Q6NZY4-1
	ZCCHC8	ENST00000536306.5	TSL:1	c.1249_1251delAAAinsCGC	p.Lys417Arg	missense	N/A	ENSP00000441423.1	Q6NZY4-2
	ZCCHC8	ENST00000543897.5	TSL:1	c.1249_1251delAAAinsCGC	p.Lys417Arg	missense	N/A	ENSP00000438993.1	Q6NZY4-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-122958203;