12-52378078-C-G

Variant names:

• chr12-52378078-C-G
• NM_033045.4:c.1759G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033045.4(KRT84):​c.1759G>C​(p.Val587Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT84 NM_033045.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0960

Genes affected

KRT84 (HGNC:6461): (keratin 84) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin is contained primarily in the filiform tongue papilla, among other hair keratins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14058435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT84	NM_033045.4	c.1759G>C	p.Val587Leu	missense_variant	Exon 9 of 9	ENST00000257951.3	NP_149034.2
KRT84	XM_011538335.3	c.1759G>C	p.Val587Leu	missense_variant	Exon 10 of 10		XP_011536637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT84	ENST00000257951.3	c.1759G>C	p.Val587Leu	missense_variant	Exon 9 of 9	1	NM_033045.4	ENSP00000257951.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1759G>C (p.V587L) alteration is located in exon 9 (coding exon 9) of the KRT84 gene. This alteration results from a G to C substitution at nucleotide position 1759, causing the valine (V) at amino acid position 587 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0048	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.18
Sift	Uncertain	0.013	D
Sift4G	Benign	0.061	T
Polyphen		0.21	B
Vest4		0.25
MutPred		0.27		Gain of catalytic residue at F589 (P = 0.0098);
MVP		0.68
MPC		0.027
ClinPred		0.75	D
GERP RS		2.8
Varity_R		0.080
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-52771862;